11-hydroxy-5h-pyrrolo[2,1-c][1,4] benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines

ABSTRACT

The present inventors have developed a key intermediate for the production of C2 substituted PBDs, which has a leaving group at the C2 position, a carbamate protecting group at the N10 position and a protected hydroxy group at the C11 position. In a first aspect, the present invention comprises a compound with a the formula (I), wherein: R 10  is a carbamate-based nitrogen protecting group; R 11  is an oxygen protecting group; and R 2  is a labile leaving group. In a further aspect, the present invention comprises a method of synthesising a compound of formula (III), or a solvate thereof, from a compound of formula (I) as defined in the first aspect, R 16  is either O—R11, wherein R 11  is as defined in the first aspect, or OH, or R 10  and R 16  together form a double bond between N10 and C11; and R 15  is R. The other substituents are defined in the claims. Further aspects of the present invention relate to compounds of formula (III) (including solvates thereof when R 10  and R 16  form a double bond between N10 and C11, and pharmaceutical salts thereof), pharmaceutical compositions comprising these, and their use in the manufacture of a medicament for the treatment of a proliferative disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a national stage filing under 35 U.S.C. 371of International Application No. PCT/GB2005/000768, filed on Mar. 1,2005, which claims foreign priority benefits to United KingdomApplication No. 0404575.3, filed Mar. 1, 2004 and United KingdomApplication No. 0426392.7, filed Dec. 1, 2004.

The present invention relates to pyrrolobenzodiazepines (PBDs), and inparticular pyrrolobenzodiazepines useful in the synthesis of C2substituted compounds.

BACKGROUND TO THE INVENTION

Some pyrrolobenzodiazepines (PBDs) have the ability to recognise andbond to specific sequences of DNA; the preferred sequence is PuGPu. Thefirst PBD antitumour antibiotic, anthramycin, was discovered in 1965(Leimgruber, et al., J. Am. Chem. Soc., 87, 5793-5795 (1965);Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)). Sincethen, a number of naturally occurring PBDs have been reported, and over10 synthetic routes have been developed to a variety of analogues(Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Family membersinclude abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148(1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206(1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem.Brit., 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758(1992)), mazethramycin (Kuminoto, et al., J. Antibiotics, 33, 665-667(1980)), neothramycins A and B (Takeuchi, et al., J. Antibiotics, 29,93-96 (1976)), porothramycin (Tsunakawa, et al., J. Antibiotics, 41,1366-1373 (1988)), prothracarcin (Shimizu, et al, J. Antibiotics, 29,2492-2503 (1982); Langley and Thurston, J. Org. Chem., 52, 91-97(1987)), sibanomicin (DC-102)(Hara, et al., J. Antibiotics, 41, 702-704(1988); Itoh, et al., J. Antibiotics, 41, 1281-1284 (1988)), sibiromycin(Leber, et al., J. Am. Chem. Soc., 110, 2992-2993 (1988)) and tomamycin(Arima, et al., J. Antibiotics, 25, 437-444 (1972)). PBDs are of thegeneral structure:

They differ in the number, type and position of substituents, in boththeir aromatic A rings and pyrrolo C rings, and in the degree ofsaturation of the C ring. In the B-ring there is either an imine(N═C), acarbinolamine(NH—CH(OH)), or a carbinolamine methyl ether (NH—CH(OMe))at the N10-C11 position which is the electrophilic centre responsiblefor alkylating DNA. All of the known natural products have an(S)-configuration at the chiral C11a position which provides them with aright-handed twist when viewed from the C ring towards the A ring. Thisgives them the appropriate three-dimensional shape for isohelicity withthe minor groove of B-form DNA, leading to a snug fit at the bindingsite (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-11(1975); Hurley and Needham-VanDevanter, Acc. Chem. Res., 19, 230-237(1986)). Their ability to form an adduct in the minor groove, enablesthem to interfere with DNA processing, hence their use as antitumouragents.

The present inventors have previously disclosed, in PCT/GB2003/004963,cytotoxic compounds having an aryl group at the C2 position, forexample:

The synthesis of these compounds was achieved via the followingintermediate:

whose synthesis was described in detail in WO 00/12508. This methodinvolves a reduction as a deprotection step, which can lead tooverreduction of the compound which is not desirable. Also, with certainC2 groups, the reduction step does not proceed at all.

The following intermediate has also been disclosed:

but its synthesis has proved difficult and only proceeds in low yield.

DISCLOSURE OF THE INVENTION

The present inventors have developed a key intermediate for theproduction of C2 substituted PBDs, which has a leaving group at the C2position, a carbamate protecting group at the N10 position and aprotected hydroxy group at the C11 position.

In a first aspect, the present invention comprises a compound with theformula I:

wherein:

-   R⁶ and R⁹ are independently selected from H, R, OH, OR, SH, SR, NH₂,    NHR, NRR′, nitro, Me₃Sn and halo;-   where R and R′ are independently selected from optionally    substituted C₁₋₁₂ alkyl, C₃₋₂₀ heterocyclyl and C₅₋₂₀ aryl groups;-   R⁷ and R⁸ are independently selected from H, R, OH, OR, SH, SR, NH₂,    NHR, NHRR′, nitro, Me₃Sn and halo, or the compound is a dimer with    each monomer being of formula (I), where the R⁷ groups or R⁸ groups    of each monomers form together a dimer bridge having the formula    —X—R″—X— linking the monomers, where R″ is a C₃₋₁₂ alkylene group,    which chain may be interrupted by one or more heteroatoms, e.g. O,    S, NH, and/or aromatic rings, e.g. benzene or pyridine, and each X    is independently selected from O, S, or NH;-   or any pair of adjacent groups from R⁶ to R⁹ together form a group    —O—(CH₂)_(p)—O—, where p is 1 or 2;-   R¹⁰ is a carbamate-based nitrogen protecting group;-   R¹¹ is an oxygen protecting group; and-   R² is a labile leaving group.

In a second aspect, the present invention comprises a method ofsynthesising a compound of formula I as defined in the first aspect ofthe invention from a compound of formula IIa:

-   wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined in the first    aspect; and-   R¹² and R¹³ together form ═O.

It is preferred that the compound of formula IIa is synthesised from acompound of formula IIb:

-   wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined in the first    aspect;-   R¹² is O—R¹⁴, and R¹³ is H, where R¹⁴ is an oxygen protecting group    which is orthogonal to R¹¹.

In a third aspect, the present invention comprises a method ofsynthesising a compound of formula III:

-   or a solvate thereof, from a compound of formula I as defined in the    first aspect, wherein R⁶, R⁷, R⁸, R⁹ are as defined in the first    aspect;-   R¹⁰ is as defined in the first aspect and R¹⁶ is either O—R¹¹,    wherein R¹¹ is as defined in the first aspect, or OH, or R¹⁰ and R¹⁶    together form a double bond between N10 and C11; and-   R¹⁵ is R.

Further aspects of the present invention relate to novel compounds offormula III (including solvates thereof when R¹⁰ and R¹⁶ form a doublebond between N10 and C11, and pharmaceutical salts thereof), their usein methods of therapy (particularly in treating proliferative diseases),pharmaceutical compositions comprising these, and their use in themanufacture of a medicament for the treatment of a proliferativedisease.

DEFINITIONS Carbamate-Based Nitrogen Protecting Groups

Carbamate-based nitrogen protecting groups are well known in the art,and have the following structure:

wherein R′¹⁰ is R as defined above. A large number of suitable groupsare described on pages 503 to 549 of Greene, T. W. and Wuts, G. M.,Protective Groups in Organic Synthesis, 3^(rd) Edition, John Wiley &Sons, Inc., 1999, which is incorporated herein by reference.

Particularly preferred protecting groups include Troc, Teoc, Fmoc, BOC,Doc, Hoc, TcBOC, 1-Adoc and 2-Adoc.

Those protecting groups which can be removed with palladium catalysisare not preferred, e.g. Alloc.

Also suitable for use in the present invention are nitrogen protectinggroup which can be removed in vivo (e.g. enzymatically, using light) asdescribed in WO 00/12507, which is incorporated herein by reference.Examples of these protecting groups include:

which is nitroreductase labile (e.g. using ADEPT/GDEPT);

which are photolabile; and

which is glutathione labile (e.g. using NPEPT).Oxygen Protecting Groups

Oxygen protecting groups are well known in the art. A large number ofsuitable groups are described on pages 23 to 200 of Greene, T. W. andWuts, G. M., Protective Groups in Organic Synthesis, 3^(rd) Edition,John Wiley & Sons, Inc., 1999, which is incorporated herein byreference.

Classes of particular interest include silyl ethers, methyl ethers,alkyl ethers, benzyl ethers, esters, benzoates, carbonates, andsulfonates.

Preferred oxygen protecting groups include TBS, THP for the C11 oxygenatom, and methyl ester for the C2 oxygen atom (where present).

As mentioned above the oxygen protecting group R¹⁴ should be orthogonalto the oxygen protecting group R¹¹. Protecting groups which areorthogonal to one another may each be removed using reagents orconditions which do not remove the other protecting group.

It may also be preferred that any protecting groups used during thesynthesis and use of compounds of formula I are orthogonal to oneanother. However, it is often not necessary, but may be desirable, forthe carbamate-based nitrogen protecting group and R¹¹ to be orthogonalto one another, depending on whether the compound of formula III is tobe used with the nitrogen protecting group in place.

Labile Leaving Groups

Labile leaving groups suitable for use in the present invention are inparticular those amenable to palladium catalysed coupling, for exampleusing Suzuki or Stille coupling. Suitable groups includemesylate(—OSO₂CH₃), —OSO₂(C_(n)F_(2n+1)) where n=0, 1 or 4, —OSO₂—R^(S)where R^(S) is an optionally substituted phenyl group (e.g. 4-Me-Ph,tosylate), I, Br and Cl. More preferred are —OSO₂(C_(n)F_(2n+1)) wheren=0, 1 or 4, I, Br and Cl, with triflate (—OSO₂CF₃) and Br being themost preferred.

Substituents

The phrase “optionally substituted” as used herein, pertains to a parentgroup which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted” as used herein,pertains to a parent group which bears one or more substitutents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, or if appropriate,fused to, a parent group. A wide variety of substituents are well known,and methods for their formation and introduction into a variety ofparent groups are also well known.

Examples of substituents are described in more detail below.

C₁₋₁₂ alkyl: The term “C₁₋₁₂ alkyl” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a carbonatom of a hydrocarbon compound having from 1 to 12 carbon atoms, whichmay be aliphatic or alicyclic, and which may be saturated or unsaturated(e.g. partially unsaturated, fully unsaturated). Thus, the term “alkyl”includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussedbelow.

Examples of saturated alkyl groups include, but are not limited to,methyl(C₁), ethyl(C₂), propyl(C₃), butyl(C₄), pentyl(C₅), hexyl(C₆) andheptyl(C₇).

Examples of saturated linear alkyl groups include, but are not limitedto, methyl(C₁), ethyl(C₂), n-propyl(C₃), n-butyl(C₄),n-pentyl(amyl)(C₅), n-hexyl(C₆) and n-heptyl(C₇).

Examples of saturated branched alkyl groups include iso-propyl(C₃),iso-butyl(C₄), sec-butyl(C₄), tert-butyl(C₄), iso-pentyl(C₅), andneo-pentyl(C₅).

C₂₋₁₂ Alkenyl: The term “C₂₋₁₂ alkenyl” as used herein, pertains to analkyl group having one or more carbon-carbon double bonds.

Examples of unsaturated alkenyl groups include, but are not limited to,ethenyl(vinyl, —CH═CH₂), 1-propenyl(—CH═CH—CH₃), 2-propenyl(allyl,—CH—CH═CH₂), isopropenyl(1-methylvinyl, —C(CH₃)═CH₂), butenyl(C₄),pentenyl(C₅), and hexenyl(C₆).

C₂₋₁₂ alkynyl: The term “C₂₋₁₂ alkynyl” as used herein, pertains to analkyl group having one or more carbon-carbon triple bonds.

Examples of unsaturated alkynyl groups include, but are not limited to,ethynyl(ethinyl, —C≡CH) and 2-propynyl(propargyl, —CH₂—C≡CH).

C₃₋₁₂ cycloalkyl: The term “C₃₋₁₂ cycloalkyl” as used herein, pertainsto an alkyl group which is also a cyclyl group; that is, a monovalentmoiety obtained by removing a hydrogen atom from an alicyclic ring atomof a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3to 7 carbon atoms, including from 3 to 7 ring atoms.

Examples of cycloalkyl groups include, but are not limited to, thosederived from:

-   -   saturated monocyclic hydrocarbon compounds: cyclopropane(C₃),        cyclobutane(C₄), cyclopentane(C₅), cyclohexane(C₆),        cycloheptane(C₇), methylcyclopropane(C₄),        dimethylcyclopropane(C₅), methylcyclobutane(C₅),        dimethylcyclobutane(C₆), methylcyclopentane(C₆),        dimethylcyclopentane(C₇) and methylcyclohexane(C₇);    -   unsaturated monocyclic hydrocarbon compounds: cyclopropene(C₃),        cyclobutene(C₄), cyclopentene(C₅), cyclohexene(C₆),        methylcyclopropene(C₄), dimethylcyclopropene(C₅),        methylcyclobutene(C₅), dimethylcyclobutene(C₆),        methylcyclopentene(C₆), dimethylcyclopentene(C₇) and        methylcyclohexene(C₇); and    -   saturated polycyclic hydrocarbon compounds: norcarane(C₇),        norpinane(C₇), norbornane(C₇).

C₃₋₂₀ heterocyclyl: The term “C₃₋₂₀ heterocyclyl” as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a ring atom of a heterocyclic compound, which moiety has from 3 to20 ring atoms, of which from 1 to 10 are ring heteroatoms. Preferably,each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ringheteroatoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl”, as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those derived from:

-   N₁: aziridine(C₃), azetidine(C₄),    pyrrolidine(tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline,    2,5-dihydropyrrole)(C₅), 2H-pyrrole or 3H-pyrrole(isopyrrole,    isoazole)(C₅), piperidine(C₆), dihydropyridine(C₆),    tetrahydropyridine(C₆), azepine(C₇);-   O₁: oxirane(C₃), oxetane(C₄), oxolane(tetrahydrofuran)(C₅),    oxole(dihydrofuran)(C₅), oxane(tetrahydropyran)(C₆),    dihydropyran(C₆), pyran(C₆), oxepin(C₇);-   S₁: thiirane(C₃), thietane(C₄), thiolane(tetrahydrothiophene)(C₅),    thiane(tetrahydrothiopyran)(C₆), thiepane(C₇);-   O₂: dioxolane(C₅), dioxane(C₆), and dioxepane(C₇);-   O₃: trioxane(C₆);-   N₂: imidazolidine(C₅), pyrazolidine(diazolidine)(C₅),    imidazoline(C₅), pyrazoline(dihydropyrazole)(C₅), piperazine(C₆);-   N₁O₁: tetrahydrooxazole(C₅), dihydrooxazole(C₅),    tetrahydroisoxazole(C₅), dihydroisoxazole(C₅), morpholine(C₆),    tetrahydrooxazine(C₆), dihydrooxazine(C₆), oxazine(C₆);-   N₁S₁: thiazoline(C₅), thiazolidine(C₅), thiomorpholine(C₆);-   N₂O₁: oxadiazine(C₆);-   O₁S₁: oxathiole(C₅) and oxathiane (thioxane)(C₆); and,-   N₁O₁S₁: oxathiazine(C₆).

Examples of substituted monocyclic heterocyclyl groups include thosederived from saccharides, in cyclic form, for example, furanoses(C₅),such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse,and pyranoses(C₆), such as allopyranose, altropyranose, glucopyranose,mannopyranose, gulopyranose, idopyranose, galactopyranose, andtalopyranose.

C₅₋₂₀ aryl: The term “C₅₋₂₀ aryl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from an aromaticring atom of an aromatic compound, which moiety has from 3 to 20 ringatoms. Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆ aryl” as used herein,pertains to an aryl group having 5 or 6 ring atoms.

The ring atoms may be all carbon atoms, as in “carboaryl groups”.Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e. phenyl)(C₆), naphthalene(C₁₀), azulene(C₁₀),anthracene(C₁₄), phenanthrene(C₁₄), naphthacene(C₁₈), and pyrene(C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indane (e.g. 2,3-dihydro-1H-indene)(C₉), indene(C₉),isoindene(C₉), tetraline(1,2,3,4-tetrahydronaphthalene(C₁₀),acenaphthene(C₁₂), fluorene(C₁₃), phenalene(C₁₃), acephenanthrene(C₁₅),and aceanthrene(C₁₆).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups”. Examples of monocyclic heteroaryl groups include,but are not limited to, those derived from:

-   N₁: pyrrole(azole)(C₅), pyridine(azine)(C₆);-   O₁: furan(oxole)(C₅);-   S₁: thiophene(thiole)(C₅);-   N₁O₁: oxazole(C₅), isoxazole(C₅), isoxazine(C₆);-   N₂O₁: oxadiazole(furazan)(C₅);-   N₃O₁: oxatriazole(C₅);-   N₁S₁: thiazole(C₅), isothiazole(C₅);-   N₂: imidazole(1,3-diazole)(C₅), pyrazole(1,2-diazole)(C₅),    pyridazine(1,2-diazine)(C₆), pyrimidine(1,3-diazine)(C₆) (e.g.,    cytosine, thymine, uracil), pyrazine(1,4-diazine)(C₆);-   N₃: triazole(C₅), triazine(C₆); and,-   N₄: tetrazole(C₅).

Examples of heteroaryl which comprise fused rings, include, but are notlimited to:

-   -   C₉ (with 2 fused rings) derived from benzofuran(O₁),        isobenzofuran(O₁), indole(N₁), isoindole(N₁), indolizine(N₁),        indoline(N₁), isoindoline(N₁), purine(N₄) (e.g., adenine,        guanine), benzimidazole(N₂), indazole(N₂), benzoxazole(N₁O₁),        benzisoxazole(N₁O₁), benzodioxole(O₂), benzofurazan(N₂O₁),        benzotriazole(N₃), benzothiofuran(S₁), benzothiazole(N₁S₁),        benzothiadiazole(N₂S);    -   C₁₀ (with 2 fused rings) derived from chromene(O₁),        isochromene(O₁), chroman(O₁), isochroman(O₁), benzodioxan(O₂),        quinoline(N₁), isoquinoline(N₁), quinolizine(N₁),        benzoxazine(N₁O₁), benzodiazine(N₂), pyridopyridine(N₂),        quinoxaline(N₂), quinazoline(N₂), cinnoline(N₂),        phthalazine(N₂), naphthyridine(N₂), pteridine(N₄);    -   C₁₁ (with 2 fused rings) derived from benzodiazepine(N₂);    -   C₁₃ (with 3 fused rings) derived from carbazole(N₁),        dibenzofuran(O₁), dibenzothiophene(S₁), carboline(N₂),        perimidine(N₂), pyridoindole(N₂); and,    -   C₁₄ (with 3 fused rings) derived from acridine(N₁),        xanthene(O₁), thioxanthene(S₁), oxanthrene(O₂),        phenoxathiin(O₁S₁), phenazine(N₂), phenoxazine(N₁O₁),        phenothiazine(N₁S₁), thianthrene(S₂), phenanthridine(N₁),        phenanthroline(N₂), phenazine(N₂).

The above groups, whether alone or part of another substituent, maythemselves optionally be substituted with one or more groups selectedfrom themselves and the additional substituents listed below.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇ alkylgroup (also referred to as a C₁₋₇ alkoxy group, discussed below), aC₃₋₂₀ heterocyclyl group (also referred to as a C₃₋₂₀ heterocyclyloxygroup), or a C₅₋₂₀ aryl group (also referred to as a C₅₋₂₀ aryloxygroup), preferably a C₁₋₇alkyl group.

Alkoxy: —OR, wherein R is an alkyl group, for example, a C₁₋₇ alkylgroup. Examples of C₁₋₇ alkoxy groups include, but are not limited to,—OMe(methoxy), —OEt(ethoxy), —O(nPr)(n-propoxy), —O(iPr)(isopropoxy),—O(nBu)n-butoxy), —O(sBu)(sec-butoxy), —O(iBu)(isobutoxy), and—O(tBu)(tert-butoxy).

Acetal: —CH(OR¹)(OR²), wherein R¹ and R² are independently acetalsubstituents, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group, or, in thecase of a “cyclic” acetal group, R¹ and R², taken together with the twooxygen atoms to which they are attached, and the carbon atoms to whichthey are attached, form a heterocyclic ring having from 4 to 8 ringatoms. Examples of acetal groups include, but are not limited to,—CH(OMe)₂, —CH(OEt)₂, and —CH(OMe)(OEt).

Hemiacetal: —CH(OH)(OR¹), wherein R¹ is a hemiacetal substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of hemiacetal groupsinclude, but are not limited to, —CH(OH)(OMe) and —CH(OH)(OEt).

Ketal: —CR(OR¹)(OR²), where R¹ and R² are as defined for acetals, and Ris a ketal substituent other than hydrogen, for example, a C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples ketal groups include, but are not limited to,—C(Me)(OMe)₂, —C(Me)(OEt)₂, —C(Me)(OMe)(OEt), —C(Et)(OMe)₂,—C(Et)(OEt)₂, and —C(Et)(OMe)(OEt).

Hemiketal: —CR(OH)(OR¹), where R¹ is as defined for hemiacetals, and Ris a hemiketal substituent other than hydrogen, for example, a C₁₋₇alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of hemiacetal groups include,but are not limited to, —C(Me)(OH)(OMe), —C(Et)(OH)(OMe),—C(Me)(OH)(OEt), and —C(Et)(OH)(OEt).

Oxo(keto, -one): ═O.

Thione(thioketone): ═S.

Imino(imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably hydrogen or a C₁₋₇ alkyl group. Examples of estergroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl(carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl(keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇ alkyl group (also referred to as C₁₋₇ alkylacyl or C₁₋₇ alkanoyl),a C₃₋₂₀ heterocyclyl group (also referred to as C₃₋₂₀ heterocyclylacyl),or a C₅₋₂₀ aryl group (also referred to as C₅₋₂₀ arylacyl), preferably aC₁₋₇ alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃(acetyl), —C(═O)CH₂CH₃(propionyl),—C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph(benzoyl, phenone).

Carboxy(carboxylic acid): —C(═O)OH.

Thiocarboxy(thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy(thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy(thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester(carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇ alkyl group, aC₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy(reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Examples of acyloxy groupsinclude, but are not limited to, —OC(═O)CH₃(acetoxy), —OC(═O)CH₂CH₃,—OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Oxycarboyloxy: —OC(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of ester groups include,but are not limited to, —OC(═O)OCH₃, —OC(═O)OCH₂CH₃, —OC(═O)OC(CH₃)₃,and —OC(═O)OPh.

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇ alkyl group (also referred to as C₁₋₇alkylamino or di-C₁₋₇ alkylamino), a C₃₋₂₀ heterocyclyl group, or aC₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group, or, in the case ofa “cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), ortertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃,—NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic aminogroups include, but are not limited to, aziridino, azetidino,pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Amido(carbamoyl, carbamyl, aminocarbonyl, carboxamide) —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Thioamido(thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof amido groups include, but are not limited to, —C(═S)NH₂, —C(═S)NHCH₃,—C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Acylamido(acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group,or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇ alkyl group, and R²is an acyl substituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of acylamide groups include, but are not limitedto, —NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may togetherform a cyclic structure, as in, for example, succinimidyl, maleimidyl,and phthalimidyl:

Aminocarbonyloxy: —OC(═O)NR¹R², wherein R¹ and R² are independentlyamino substituents, as defined for amino groups. Examples ofaminocarbonyloxy groups include, but are not limited to, —OC(═O)NH₂,—OC(═O)NHMe, —OC(═O)NMe₂, and —OC(═O)NEt₂.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of ureido groups include, but are not limited to,—NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Imino: ═NR, wherein R is an imino substituent, for example, for example,hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples of imino groupsinclude, but are not limited to, ═NH, ═NMe, and ═NEt.

Amidine(amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group,or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Nitroso: —NO.

Azido: —N₃.

Cyano(nitrile, carbonitrile): —CN.

Isocyano: —NC.

Cyanato: —OCN.

Isocyanato: —NCO.

Thiocyano(thiocyanato): —SCN.

Isothiocyano(isothiocyanato): —NCS.

Sulfhydryl(thiol, mercapto): —SH.

Thioether(sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇ alkyl group (also referred to as a C₁₋₇alkylthio group),a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇alkyl group. Examples of C₁₋₇ alkylthio groups include, but are notlimited to, —SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group (also referred to herein as C₁₋₇ alkyldisulfide). Examples of C₁₋₇ alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfine(sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfine groups include, but are not limited to, —S(═O)CH₃ and—S(═O)CH₂CH₃.

Sulfone(sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇ alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃(methanesulfonyl,mesyl), —S(═O)₂CF₃(triflyl), —S(═O)₂CH₂CH₃(esyl), —S(═O)₂C₄F₉(nonaflyl),—S(═O)₂CH₂CF₃(tresyl), —S(═O)₂CH₂CH₂NH₂(tauryl),—S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl(tosyl),4-chlorophenylsulfonyl(closyl), 4-bromophenylsulfonyl(brosyl),4-nitrophenyl(nosyl), 2-naphthalenesulfonate(napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate(dansyl)

Sulfinic acid(sulfino): —S(═O)OH, —SO₂H.

Sulfonic acid(sulfo): —S(═O)₂OH, —SO₃H.

Sulfinate(sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfinate groups include, but are not limited to,—S(═O)OCH₃(methoxysulfinyl; methyl sulfinate) and—S(═O)OCH₂CH₃(ethoxysulfinyl; ethyl sulfinate).

Sulfonate (sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfonate groups include, but are not limited to,—S(═O)₂OCH₃(methoxysulfonyl; methyl sulfonate) and—S(═O)₂OCH₂CH₃(ethoxysulfonyl; ethyl sulfonate).

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃ (mesylate) and—OS(═O)₂CH₂CH₃ (esylate).

Sulfate: —OS(═O)₂OR; wherein R is a sulfate substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfate groups include, butare not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.

Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): —S(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of sulfamyl groups include, but are not limitedto, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃),—S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

Phosphino (phosphine): —PR₂, wherein R is a phosphino substituent, forexample, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably —H, a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group.Examples of phosphino groups include, but are not limited to, —PH₂,—P(CH₃)₂, —P(CH₂CH₃)₂, —P(t-Bu)₂, and —P(Ph)₂.

Phospho: —P(═O)₂.

Phosphinyl (phosphine oxide): —P(═O)R₂, wherein R is a phosphinylsubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group or a C₅₋₂₀aryl group. Examples of phosphinyl groups include, but are not limitedto, —P(═O)(CH₃)₂, —P(═O)(CH₂CH₃)₂, —P(═O)(t-Bu)₂, and —P(═O)(Ph)₂.

Phosphonic acid (phosphono): —P(═O)(OH)₂.

Phosphonate (phosphono ester): —P(═O)(OR)₂, where R is a phosphonatesubstituent, for example, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably —H, a C₁₋₇ alkyl group, or aC₅₋₂₀ aryl group. Examples of phosphonate groups include, but are notlimited to, —P(═O)(OCH₃)₂, —P(═O)(OCH₂CH₃)₂, —P(═O)(O-t-Bu)₂, and—P(═O)(OPh)₂.

Phosphoric acid (phosphonooxy): —OP(═O)(OH)₂.

Phosphate (phosphonooxy ester): —OP(═O)(OR)₂, where R is a phosphatesubstituent, for example, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably —H, a C₁₋₇ alkyl group, or aC₅₋₂₀ aryl group. Examples of phosphate groups include, but are notlimited to, —OP(═O)(OCH₃)₂, —OP((═O)(OCH₂CH₃)₂, —OP(═O)(O-t-Bu)₂, and—OP(═O)(OPh)₂.

Phosphorous acid: —OP(OH)₂.

Phosphite: —OP(OR)₂, where R is a phosphite substituent, for example,—H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably —H, a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group.Examples of phosphite groups include, but are not limited to,—OP(OCH₃)₂, —OP(OCH₂CH₃)₂, —OP(O-t-Bu)₂, and —OP(OPh)₂.

Phosphoramidite: —OP(OR¹)—NR² ₂, where R¹ and R² are phosphoramiditesubstituents, for example, —H, a (optionally substituted) C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably —H,a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group. Examples of phosphoramiditegroups include, but are not limited to, —OP(OCH₂CH₃)—N(CH₃)₂,—OP(OCH₂CH₃)—N(i-Pr)₂, and —OP(OCH₂CH₂CN)—N(i-Pr)₂.

Phosphoramidate: —OP(═O)(OR¹)—NR² ₂, where R¹ and R² are phosphoramidatesubstituents, for example, —H, a (optionally substituted) C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably —H,a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group. Examples of phosphoramidategroups include, but are not limited to, —OP(═O)(OCH₂CH₃)—N(CH₃)₂,—OP(═O)(OCH₂CH₃)—N(i-Pr)₂, and —OP(═O)(OCH₂CH₂CN)—N(i-Pr)₂.

Alkylene

C₃₋₁₂ alkylene: The term “C₃₋₁₂ alkylene”, as used herein, pertains to abidentate moiety obtained by removing two hydrogen atoms, either bothfrom the same carbon atom, or one from each of two different carbonatoms, of a hydrocarbon compound having from 3 to 12 carbon atoms(unless otherwise specified), which may be aliphatic or alicyclic, andwhich may be saturated, partially unsaturated, or fully unsaturated.Thus, the term “alkylene” includes the sub-classes alkenylene,alkynylene, cycloalkylene, etc., discussed below.

Examples of linear saturated C₃₋₁₂ alkylene groups include, but are notlimited to, —(CH₂)_(n)— where n is an integer from 3 to 12, for example,—CH₂CH₂CH₂— (propylene), —CH₂CH₂CH₂CH₂— (butylene), —CH₂CH₂CH₂CH₂CH₂—(pentylene) and —CH₂CH₂CH₂CH₂CH₂CH₂CH₂— (heptylene).

Examples of branched saturated C₃₋₁₂ alkylene groups include, but arenot limited to, —CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH(CH₂CH₃)—, —CH(CH₂CH₃)CH₂—, and—CH₂CH(CH₂CH₃)CH₂—.

Examples of linear partially unsaturated C₃₋₁₂ alkylene groups (C₃₋₁₂alkenylene, and alkynylene groups) include, but are not limited to,—CH═CH—CH₂—, —CH₂—CH═CH₂—, —CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH═CH—CH₂—, —CH═CH—CH═CH—CH₂—CH₂—,—CH═CH—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—CH═CH—, and —CH₂—C≡C—CH₂—.

Examples of branched partially unsaturated C₃₋₁₂ alkylene groups (C₃₋₁₂alkenylene and alkynylene groups) include, but are not limited to,—C(CH₃)═CH—, —C(CH₃)═CH—CH₂—, —CH═CH—CH(CH₃)— and —C≡C—CH(CH₃)—.

Examples of alicyclic saturated C₃₋₁₂ alkylene groups (C₃₋₁₂cycloalkylenes) include, but are not limited to, cyclopentylene (e.g.cyclopent-1,3-ylene), and cyclohexylene (e.g. cyclohex-1,4-ylene).

Examples of alicyclic partially unsaturated C₃₋₁₂ alkylene groups (C₃₋₁₂cycloalkylenes) include, but are not limited to, cyclopentenylene (e.g.4-cyclopenten-1,3-ylene), cyclohexenylene (e.g. 2-cyclohexen-1,4-ylene;3-cyclohexen-1,2-ylene; 2,5-cyclohexadien-1,4-ylene).

Proliferative Diseases

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a proliferative condition for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

The term “proliferative disease” pertains to an unwanted or uncontrolledcellular proliferation of excessive or abnormal cells which isundesired, such as, neoplastic or hyperplastic growth, whether in vitroor in vivo.

Examples of proliferative conditions include, but are not limited to,benign, pre-malignant, and malignant cellular proliferation, includingbut not limited to, neoplasms and tumours (e.g. histocytoma, glioma,astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer,gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma,ovarian carcinoma, prostate cancer, testicular cancer, liver cancer,kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma,osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g. of connective tissues), andatherosclerosis.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g. bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

Methods of Treatment

As described above, the present invention provide the use of a compoundof formula III in a method of therapy. Also provided is a method oftreatment, comprising administering to a subject in need of treatment atherapeutically-effective amount of a compound of formula III,preferably in the form of a pharmaceutical composition, which is thethird aspect of the present invention. The term “therapeuticallyeffective amount” is an amount sufficient to show benefit to a patient.Such benefit may be at least amelioration of at least one symptom. Theactual amount administered, and rate and time-course of administration,will depend on the nature and severity of what is being treated.Prescription of treatment, e.g. decisions on dosage, is within theresponsibility of general practitioners and other medical doctors.

A compound may be administered alone or in combination with othertreatments, either simultaneously or sequentially dependent upon thecondition to be treated. Examples of treatments and therapies include,but are not limited to, chemotherapy (the administration of activeagents, including, e.g. drugs; surgery; and radiation therapy. If thecompound of formula III bears a carbamate-based nitrogen protectinggroup which may be removed in vivo, then the methods of treatmentdescribed in WO 00/12507 (ADEPT, GDEPT and PDT) may be used.

Pharmaceutical compositions according to the present invention, and foruse in accordance with the present invention, may comprise, in additionto the active ingredient, i.e. a compound of formula III, apharmaceutically acceptable excipient, carrier, buffer, stabiliser orother materials well known to those skilled in the art. Such materialsshould be non-toxic and should not interfere with the efficacy of theactive ingredient. The precise nature of the carrier or other materialwill depend on the route of administration, which may be oral, or byinjection, e.g. cutaneous, subcutaneous, or intravenous.

Pharmaceutical compositions for oral administration may be in tablet,capsule, powder or liquid form. A tablet may comprise a solid carrier oran adjuvant. Liquid pharmaceutical compositions generally comprise aliquid carrier such as water, petroleum, animal or vegetable oils,mineral oil or synthetic oil. Physiological saline solution, dextrose orother saccharide solution or glycols such as ethylene glycol, propyleneglycol or polyethylene glycol may be included. A capsule may comprise asolid carrier such a gelatin.

For intravenous, cutaneous or subcutaneous injection, or injection atthe site of affliction, the active ingredient will be in the form of aparenterally acceptable aqueous solution which is pyrogen-free and hassuitable pH, isotonicity and stability. Those of relevant skill in theart are well able to prepare suitable solutions using, for example,isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection,Lactated Ringer's Injection. Preservatives, stabilisers, buffers,antioxidants and/or other additives may be included, as required.

Includes other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms.

Isomers, Salts and Solvates

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms, c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Preferably compounds of the present invention have the followingstereochemistry at the C11 position:

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers”, as used herein, are structural (orconstitutional) isomers (i.e. isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g. C₁₋₇ alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain too tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H(D), and ³H(T); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.asymmetric synthesis) and separation (e.g. fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Example s of pharmaceuticallyacceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66,1-19 (1977).

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g. —COOH may be —COO⁻), then a salt may be formed witha suitable cation. Examples of suitable inorganic cations include, butare not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e. NH₄ ⁺) and substituted ammonium ions (e.g. NH₃R⁺, NH₂R₂ ⁺,NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g. —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

A particular salt form of interest can be formed from compounds offormula III, where R¹⁰ and R¹⁶ form an imine bond, by reacting saidcompound with a bisulphite salt to form a bisulphite derivative of thePBD. These compounds can be represented as:

where M is a monovalent pharmaceutically acceptable cation, or if thecompound is a dimer, the two M groups may together represent a divalentpharmaceutically acceptable cation, and the other groups are aspreviously defined.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

Solvates of particular relevance to the present invention are thosewhere the solvent adds across the imine bond of the PBD moiety, which isillustrated below where the solvent is water or an alcohol (R^(A)OH,where R^(A) is an ether substituent as described above):

These forms can be called the carbinolamine and carbinolamine etherforms of the PBD. The balance of these equilibria depend on theconditions in which the compounds are found, as well as the nature ofthe moiety itself.

In general any nucleophilic solvent is capable of forming such solvatesas illustrated above for hydroxylic solvents. Other nucleophilicsolvents include thiols and amines.

These solvates may be isolated in solid form, for example, bylyophilisation.

General Synthetic Routes

The synthesis of PBD compounds is extensively discussed in WO 00/12508,which discussion is incorporated herein by reference.

As discussed in that patent application, a key step in a preferred routeto PBDs is a cyclisation to produce the B-ring, involving generation ofan aldehyde (or functional equivalent thereof) at what will be the11-position, and attack thereon by the Pro-N10-nitrogen:

wherein the substituents are as defined in the second aspect of theinvention. The “masked aldehyde” —CPQ may be an acetal or thioacetal, inwhich case the cyclisation involves unmasking. Alternatively, it may bean alcohol —CHOH, in which case the reaction involves oxidation, e.g. bymeans of TPAP, TEMPO or DMSO (Swern oxidation).

In this reaction, R¹² is preferably O—R¹⁴, i.e. a protected hydroxygroup, and R¹³ is H.

The masked aldehyde compound can be produced by condensing acorresponding 2,4-substituted pyrrolidine with a 2-nitrobenzoic acid:

The nitro group can then be reduced to —NH₂ and protected by reactionwith a suitable agent, e.g. a chloroformate, which provides theremovable nitrogen protecting group in the compound of formula IV.

A process involving the oxidation-cyclization procedure is illustratedin scheme 1 (an alternative type of cyclisation will be described laterwith reference to scheme 2).

Exposure of the alcohol (B) (in which the Pro-N10-nitrogen is generallyprotected as carbamate) to tetrapropylammonium perruthenate(TPAP)/N-methylmorpholine N-oxide (NMO) over A4 sieves results inoxidation accompanied by spontaneous B-ring closure to afford thedesired product IV. The TPAP/NMO oxidation procedure is found to beparticularly convenient for small scale reactions while the use ofDMSO-based oxidation methods, particularly Swern oxidation, provessuperior for larger scale work (e.g. >1 g). A particularly preferredoxidising agent is (diacetoxyiodo)benzene (1.1 eq) and TEMPO (0.1 eq)dissolved in CH₂Cl₂.

The uncyclized alcohol (B) may be prepared by the reaction of a nitrogenprotection reagent of formula D, which is preferably a chloroformate oracid chloride, to a solution of the amino alcohol C, generally insolution, generally in the presence of a base such as pyridine(preferably 2 equivalents) at a moderate temperature (e.g. at 0° C.).Under these conditions little or no O-acylation is usually observed.

The key amino alcohol C may be prepared by reduction of thecorresponding nitro compound E, by choosing a method which will leavethe rest of the molecule intact. Treatment of E with tin (II) chloridein a suitable solvent, e.g. refluxing methanol, generally affords, afterthe removal of the tin salts, the desired product in high yield.

Exposure of E to hydrazine/Raney nickel avoids the production of tinsalts and may result in a higher yield of C, although this method isless compatible with the range of possible C and A-ring substituents.For instance, if there is C-ring unsaturation (either in the ringitself, or in R₂ or R₃), this technique may be unsuitable. Anothersuitable means of reduction would be catalytic hydrogenation usingpalladium on carbon as a catalyst.

The nitro compound of formula E may be prepared by coupling theappropriate o-nitrobenzoyl chloride to a compound of formula F, e.g. inthe presence of K₂CO₃ at −25° C. under a N₂ atmosphere. Compounds offormula F can be readily prepared, for example by olefination of theketone derived from L-trans-hydroxy proline. The ketone intermediate canalso be exploited by conversion to the enol triflate for use inpalladium mediated coupling reactions.

The o-nitrobenzoyl chloride is synthesised from the o-nitrobenzoic acid(or alkyl ester after hydrolysis) of formula G, which itself is preparedfrom the vanillic acid (or alkyl ester) derivative H. Many of these arecommercially available and some are disclosed in Althuis, T. H. andHess, H. J., J. Medicinal Chem., 20(1), 146-266 (1977).

Alternative Cyclisation (Scheme 2)

In scheme 1, the final or penultimate step was an oxidative cyclisation.An alternative, using thioacetal coupling, is shown in scheme 2.Mercury-mediated unmasking causes cyclisation to the protected PBDcompound IV.

The thioacetal compound may be prepared as shown in scheme 2: thethioacetal protected C-ring [prepared via a literature method: Langley,D. R. & Thurston, D. E., J. Organic Chemistry, 52, 91-97 (1987)] iscoupled to the o-nitrobenzoic acid (or alkyl ester after hydrolysis) (G)using a literature procedure. The resulting nitro compound cannot bereduced by hydrogenation, because of the thioacetal group, so thetin(II) chloride method is used to afford the amine. This is thenN-protected, e.g., by reaction with a chloroformate or acid chloride,such as 2,2,2-trichloroethylchloroformate.

Acetal-containing C-rings can be used as an alternative in this type ofroute with deprotection involving other methods, including the use ofacidic conditions.

Dimer Synthesis (Scheme 3)

PBD dimers may be synthesized using the strategy developed for thesynthesis of the protected PBD monomers. The synthesis routesillustrated in scheme 3 show compounds when the dimer linkage is of theformula —O—(CH₂)_(n)—O—. The step of dimer formation is normally carriedout to form a bis(nitro acid) G′. This compound can then be treated ascompound G in either scheme 1 or scheme 2 above.

The bis(nitro acid) G′ may be obtained by nitrating (e.g. using 70%nitric acid) the bis(carboxylic acid). This can be synthesised byalkylation of two equivalents of the relevant benzoic acid with theappropriate diiodoalkane under basic conditions. Many benzoic acids arecommercially available and others can be synthesised by conventionalmethods. Alternatively, the relevant benzoic acid esters can be joinedtogether by a Mitsunobu etherification with an appropriate alkanediol,followed by nitration, and then hydrolysis (not illustrated).

An alternative synthesis of the bis(nitro acid) involves oxidation ofthe bis(nitro aldehyde), e.g. with potassium permanganate. This can beobtained in turn by direct nitration of the bis(aldehyde), e.g. with 70%HNO₃. Finally, the bis(aldehyde) can be obtained via the Mitsunobuetherification of two equivalents of the benzoic aldehyde with theappropriate alkanediol.

Alternative Routes to PBDs

Alternative methods of synthesising N10 protected PBDs are disclosed inco-pending application PCT/GB2004/003873 (filed 10 Sep. 2004) whichclaims priority from GB0321295.8 (filed 11 Sep. 2003), which describesthe use of isocyanate intermediates.

Formation of Compound of formula I

Following cyclisation to form the B-ring, the C11-alcohol IV is thenpreferably re-protected, by conventional means to provide IIb. Forexample, if R¹¹ is TBS, the protection can take place by reacting IVwith TBSOTf and 2,6-lutidine. Cleavage of the C2-protecting group fromIIb then provides the C2 alcohol. For example, where the C2 protectinggroup (R¹⁴) is acyl, this deprotection may be performed by addition ofan aqueous solution of K₂CO₃.

This reprotection at the C11 position and deprotection of the C2 alcoholallows subsequent reaction of selectively the C2 alcohol positionleaving the C11 position unaffected.

The C2-alcohol may then be oxidized to the ketone IIb. Preferably thisoxidation is performed under Swern conditions, in good yield. However,other oxidation methods involving TPAP or the Dess Martin reagent alsoprovide the ketone in good yield.

If R² in the compound of formula I is —OSO₂CH₃, —OSO₂(C_(n)F_(2n+1))where n=0, 1 or 4, or —OSO₂R^(s), then the conversion from IIb may beachieved by treatment with the appropriate anhydride. For example, if R²is triflate that reaction with trifluoromethanesulfonic anhydride n DAMin the presence of pyridine.

If R² in the compound of formula I is —I or —Br, then the conversionfrom IIb may be achieved by reaction with hydrazine and iodine orbromine respectively.

If R² in the compound of formula I is —Cl, then the conversion from IIbmay be achieved by reaction with a phosphorous oxychloride (e.g. POCl₃).

Synthesis of Compounds of Formula III

This compound of formula I may be reacted under a variety of conditionsto yield PBD precursor molecules with pendant groups coupled at the C2position IIIc.

In particular, the use of palladium catalysed coupling is preferred,such as Suzuki, Stille and Heck coupling. The palladium catalyst may beany suitable catalyst, for example Pd(PPh₃)₄, Pd(OCOCH₃)₂, PdCl₂,Pd(dba)₃. The compounds which are coupled may be any suitable reactant,e.g. for Heck, alkenes with an sp² H; for Stille, organostannanes; andfor Suzuki, organoboron derivatives.

In a preferred aspect of the invention, the coupling may be performedunder microwave conditions. Typically, the palladium catalyst, such asPd(PPh₃)₄, is solid supported, for example on polystyrene, to facilitatework-up and allow potential recycling of catalyst. Unreacted boronicacid can be sequestered following complete consumption of triflate usingPS-DEAM, with a phase separator cartridge being used to isolate thecoupling product. Such a method allows for the parallel synthesis ofmore than one (e.g. up to 10, 20 or 30) compound at the same time.

The imine bond in the compound of formula IIIc can be unprotected bystandard methods to yield the unprotected compound IIIa (which may be inits carbinolamine or carboinolamine ether form, depending on thesolvents used). For example if R¹⁰ is Alloc, then the deprotection iscarried using palladium to remove the N10 protecting group, followed bythe elimination of water. If R¹⁰ is Troc, then the deprotection iscarried out using a Cd/Pb couple to yield the compound of formula IIIa.

If the nitrogen protecting group (R¹⁰) is such that the desired endproduct still contains it, e.g. if it is removable in vivo, then thecompound of formula IIIb may be synthesised by removal of the oxygenprotecting groups under suitable conditions.

Further Preferences

The following preferences may apply to all aspects of the invention asdescribed above, or may relate to a single aspect. The preferences maybe combined together in any combination.

R⁶ to R⁹

If the compound is a dimer, it is preferred that the dimer bridge is offormula —O—(CH₂)_(n)—O—, where n is from 3 to 12, and more preferably 3to 7. It is preferred that the substituents R⁸ join to form the dimerbridge.

R⁹ is preferably H.

R⁶ is preferably selected from H, OH, OR, SH, NH₂, nitro and halo, andis more preferably H or halo, and most preferably is H.

R⁷ and R⁸ (when the compound is not a dimer) are preferablyindependently selected from H, OH, OR, SH, SR, NH₂, NHR, NRR′, and halo,and more preferably independently selected from H, OH and OR, where R ispreferably selected from optionally substituted C₁₋₇ alkyl, C₃₋₁₀heterocyclyl and C₅₋₁₀ aryl groups. Particularly preferred substituentsat the 7- and 8-positions are OMe and OCH₂Ph.

In the first aspect of the invention, R¹⁰ is preferably Troc. R¹¹ ispreferably a silyl oxygen protecting group (more preferably TBS) or THP.R² is preferably triflate. Accordingly, in a particularly preferredembodiment of the first aspect of the invention, R¹⁰ is Troc, R¹¹ is TBSor THP and R² is triflate.

In the second aspect of the invention, R¹⁴ is preferably a methyl ester.R¹¹ is preferably a silyl oxygen protecting group (more preferably TBS)or THP. Accordingly, in a particularly preferred embodiment of thesecond aspect of the invention R¹⁴ is a methyl ester and R¹¹ is TBS orTHP. Furthermore, R¹⁰ is preferably Troc.

In some embodiments of the third aspect of the invention, R¹⁰ ispreferably Troc and R¹⁶ is O—R¹¹, wherein R¹¹ is preferably a silyloxygen protecting group (more preferably TBS) or THP.

In other embodiments of the third aspect of the invention, R¹⁰ and R¹⁶together form a double bond between N10 and C11.

In the third aspect of the invention R¹⁵ is preferably selected fromoptionally substituted C₅₋₂₀ aryl groups and optionally substituted C₁₋₇alkyl groups, which group has a carbon-carbon double or triple bondconjugated to the double bond in the C-ring.

Novel compounds of the present invention preferably have R¹⁰ and R¹⁶forming a double bond between N10 and C11. Preferably, the novelcompounds of the invention are dimers through C8, i.e. the R⁸ groups ofeach monomer form together a dimer bridge having the formula —X—R″—X—linking the monomers. More preferably, the dimer bridge is of formula—O—(CH₂)_(n)—O—, where n is 3 to 12, more preferably 3, 5, or 7. Thepreferences for R⁶, R⁷ and R⁹ are as expressed above. R¹⁵ is preferablyselected from:

-   (i) optionally substituted C₅₋₂₀ aryl groups;-   (ii) substituted C₂ alkyl groups; and-   (iii) optionally substituted C₃₋₇ alkyl groups.

In particular groups (ii) and (iii) above, preferably have acarbon-carbon double or triple bond conjugated to that between C2 andC3.

Group (i) above are more preferably optionally substituted C₅₋₇ arylgroups, and most preferably optionally substituted phenyl groups.

Group (ii) is preferably either a vinyl group substituted with an amidogroup, and more preferably with an amido group which is —C(═O)N(CH₃)₂;or a ethynyl group substituted with an optionally substituted C₅₋₇ arylgroup, more preferably phenyl.

Group (iii) is preferably an optionally substituted propylene group, forexample —CH═CH—CH₃.

If R is optionally substituted C₁₋₁₂ alkyl, it is preferred that it isoptionally substituted C₁₋₇ alkyl.

EXAMPLES Example 1 Formation of key Dimer Intermediate(2-[[(trifluoromethyl)sulfonyl]oxy]-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](13))(2S,4R)-N-(Benzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine(1)

Compound 1 is formed in high yield in a four step process known in theart starting from trans-4-hydroxy-L-proline (S. J. Gregson et al., J.Med. Chem., 2004, 1161-1174).

(2S,4R)-N-(Benzyloxycarbonyl-2-t-butyldimethylsilyloxymethyl-4-oxyacetylpyrrolidine(2)

(a) pyridine, Ac₂O, DMAP, THF, 16 h, 96%;

Pyridine (18.3 g, 18.7 mL, 232 mmol, 1.1 eq), acetic anhydride (23.6 g,21.8 mL, 232 mmol, 1.1 eq) and DMAP (5.14 g, 42.1 mmol, 0.2 eq) wereadded to a stirred solution of 1 (76.9 g, 211 mmol) in dry THF (1 L).The reaction mixture was stirred for 16 hours after which time TLC (95:5v/v CHCl₃/MeOH) showed the complete consumption of starting material.Excess solvent was removed by rotary evaporation and the residue wasdissolved in EtOAc (1 L), washed with 1N HCl (2×1 L), H₂O (1 L), brine(1 L) and dried (MgSO₄). Filtration and evaporation of the solventafforded acetate 2 as a colourless oil (80.7 g, 94%): ¹H NMR (400 MHz,CDCl₃) (rotamers) δ 7.36-7.12 (m, 5H), 5.30-5.10 (m, 3H), 4.09-3.97 (m,2H), 3.74-3.55 (m, 3H), 2.36-2.29 (m, 1H), 2.11-2.06 (m, 1H), 2.02 (s,3H), 0.87 (s, 6H), 0.86 (s, 3H), 0.03 and 0.00 (s×2, 6H); MS (ES), m/z(relative intensity) 430 ([M+Na]^(+.), 95), 408 ([M+H]^(+.), 100).

(2S,4R)-2-t-Butyldimethylsilyloxymethyl-4-oxyacetylpyrrolidine (3)

A slurry of silyl ether 2 (1.95 g, 4.80 mmol) and 10% Pd/C (0.17 g) inabsolute ethanol (10 mL) was subjected to Parr hydrogenation at 45 Psifor 16 h after which time TLC (95:5 v/v CHCl₃/MeOH) showed the completeconsumption of starting material. The reaction mixture was filteredthrough celite to remove the Pd/C, and the filter pad was washedrepeatedly with ethanol. Excess solvent was removed by rotaryevaporation under reduced pressure to afford the amine 3 as a paleorange waxy oil (1.28 g, 98%): IR (CHCl₃) 3315, 2930, 2858, 1739, 1652,1472, 1435, 1375, 1251, 1088, 838, 779, 667 cm⁻¹.

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2S,4R)-(5-methoxy-2-nitro-1,4-phenylene)carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine](5)

A catalytic amount of DMF (2 drops) was added to a stirred solution ofthe nitro-acid 4 (8.12 g, 17.4 mmol)¹ and oxalyl chloride (3.80 mL, 5.52g, 43.5 mmol, 2.5 eq) in dry THF (250 mL). The initial precipitatedissolved gradually and the reaction mixture was allowed to stir for 16h at room temperature. The resulting acid chloride solution was addeddropwise to a stirred mixture of the amine 3 (11.9 g, 43.5 mmol, 2.5eq), TEA (9.71 mL, 7.05 g, 69.7 mmol, 4.0 eq) and H₂O (2.26 mL) in THF(100 mL) at 0° C. (ice/acetone) under a nitrogen atmosphere. Thereaction mixture was allowed to warm to room temperature and stirred fora further 2.5 h. Excess THF was removed by rotary evaporation and theresulting residue was partitioned between H₂O (400 mL) and EtOAc (400mL). The layers were allowed to separate and the aqueous layer wasextracted with EtOAc (3×200 mL). The combined organic layers were thenwashed with saturated NH₄Cl (200 mL), saturated NaHCO₃ (200 mL), brine(200 mL) and dried (MgSO₄). Filtration and evaporation of the solventgave the crude product as a dark oil. Purification by flashchromatography (99.7:0.3 v/v CHCl₃/MeOH) isolated the pure amide 5 as alight yellow glass (13.3 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.60 (s,2H), 6.60 (s, 2H), 5.06 (br s, 2H), 4.44 (br s, 2H), 4.25-4.20 (m, 4H),4.10-4.08 (m, 2H), 3.80 (s, 6H), 3.64-3.62 (m, 2H), 3.36-3.32 (m, 2H),3.11-3.08 (m, 2H), 2.36-2.26 (m, 4H), 2.13-2.08 (m, 2H), 1.92 (s, 6H),0.80 (s, 18H), 0.00 (s×2, 12H); ¹³C NMR (100.6 MHz, CDCl₃) δ 171.0,166.3, 154.5, 148.2, 137.4, 128.0, 127.2, 109.2, 108.5, 72.9, 65.6,62.6, 57.4, 56.5, 54.8, 33.0, 28.6, 25.8, 21.0, 18.1; MS (ES), m/z(relative intensity) 1000 ([M+Na]^(+.), 39), 978 ([M+H]^(+.), 63), 977(M^(+.), 100), 812 (13).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2S,4R)-(5-methoxy-2-amino-1,4-phenylene)carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine](6)

Sodium dithionite (16.59 g, 95.27 mmol, 5 eq) was added to a stirredsolution of amide 5 (18.6 g, 19.1 mmol) in H₂O (200 mL) and THF (400mL). The reaction mixture was allowed to stir for 36 h after which timeexcess THF was removed by rotary evaporation and the resulting residuewas extracted with EtOAc (3×250 mL). The combined organic layers werethen washed with H₂O (300 mL), brine (300 mL) and dried (MgSO₄).Filtration and evaporation of the solvent yielded the crude productwhich was purified by flash chromatography (80:20 v/v hexane/EtOAc thengradient to neat EtOAc) to afford the product 6 as a yellow foam (9.53g, 55%): ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 6.70 and 6.67 (s×2, 2H),6.25 and 6.23 (s×2, 2H), 5.20 (br s, 2H), 4.49 (br s, 4H), 4.16-4.05 (m,6H), 3.70 (s, 6H), 3.68-3.57 (m, 4H), 2.36-2.27 (m, 4H), 2.12-2.04 (m,2H), 1.96 (s, 6H), 0.85 (s, 18H), 0.01 and 0.00 (s×2, 12H); ¹³C NMR(100.6 MHz, CDCl₃) δ 170.6, 170.0, 141.1, 116.3, 113.1, 102.3, 102.1,102.0, 66.2, 65.3, 65.2, 57.0, 28.9, 18.2; MS (ES), m/z (relativeintensity) 946 (M^(+.)+29, 43), 933 ([M+16]^(+.), 61), 932 ([M+15]^(+.),100), 918 ([M+H]^(+.), 72).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2S,4R)-[5-methoxy-1,4-phenylene-2-(2,2,2-trichloroethoycarbonylamino)]carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine](7)

A solution of 2,2,2-trichloroethyl chloroformate (3.58 mL, 5.50 g, 26.0mmol, 2.2 eq) in dry DCM (60 mL) was added dropwise to a solution ofanhydrous pyridine (3.82 mL, 3.80 g, 47.2 mmol, 4.0 eq) and bis-aniline6 (10.8 g, 11.8 mmol) in dry DAM (150 mL) at −10° C. (liq.N₂/ethanediol). After 16 h at room temperature, the reaction mixture waswashed with saturated NH₄Cl (2×150 mL), saturated CuSO₄ (150 mL), H₂O(150 mL), brine (150 mL) and dried (MgSO₄). Filtration and evaporationof the solvent yielded a yellow viscous oil which was purified by flashchromatography (70:30 v/v hexane/EtOAc) to afford the product 7 as awhite glass (13.8 g, 92%): ¹H NMR (400 MHz, CDCl₃) δ 9.42 (br s, 1H),7.83 (s, 2H), 6.76 and 6.74 (s×2, 2H), 5.21 (br s, 2H), 4.79 and 4.73(d×2, 4H, J=12.0 Hz), 4.56 (br s, 2H), 4.26-4.23 (m, 4H), 4.09-4.04 (m,2H), 3.74 (s, 6H), 3.72-3.68 (m, 2H), 3.60 (br s, 4H), 2.40-2.32 (m,4H), 2.23-2.08 (m, 2H), 1.95 (s, 6H), 0.85 (s, 18H), 0.01 and 0.00 (s×2,12H); ¹³C NMR (100.6 MHz, CDCl₃) δ 170.4, 169.2, 151.9, 151.5, 150.8,143.4, 132.6, 114.4, 111.7, 95.3, 74.4, 65.5, 65.4, 57.3, 56.4, 32.5,28.8, 25.8, 21.1, 18.1, 14.9; MS (ES), m/z (relative intensity) 1306([M+38]^(+.), 92), 1304 ([M+36]^(+.), 100), 1282 ([M+14]^(+.), 97), 1280([M+12]^(+.), 55).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2S,4R)-[5-methoxy-1,4-phenylene-2-(2,2,2-trichloroethoxycarbonylamino)]carbonyl]]bis(2-hydroxymethyl-4-oxyacetylpyrrolidine)(8)

A mixture of glacial acetic acid (310 mL) and H₂O (100 mL) was added toa solution of 7 (13.8 g, 10.9 mmol) in THF (250 mL) and was stirred for16 h at room temperature. The reaction mixture was diluted with DCM (750mL) and neutralised with saturated NaHCO₃ (5 L). The aqueous layer wasextracted with DAM (3×500 mL) and the organic layers were combined,washed with brine (1 L) and dried (MgSO₄). TLC (60:40 v/v hexane/EtOAc)revealed the complete disappearance of the starting material. Filtrationand evaporation of the solvent afforded the crude product which waspurified by flash column chromatography (99.7:0.3 v/v CHCl₃/MeOH thengradient to 96:4 v/v CHCl₃/MeOH) to provide the product 8 as a whiteglass (11.6 g, >100%): ¹H NMR (500 MHz, CDCl₃) δ 8.92 (br s, 2H), 7.55(s, 1H), 6.71 (s, 1H), 5.18 (br s, 2H), 4.78 (d, 2H, J=12.0 Hz), 4.72(d, 2H, J=12.0 Hz), 4.50 (br s, 2H), 4.22-4.19 (m, 4H), 4.00 (br s, 2H),3.78 (s, 6H), 3.76-3.52 (m, 6H), 2.32-2.30 (m, 2H), 2.21-2.17 (m, 2H),2.09-2.04 (m, 2H) 1.94 (s, 6H); ¹³C NMR (125.8 MHz, CDCl₃) δ 170.4,152.2, 149.8, 145.0, 111.3, 106.5, 95.6, 74.4, 72.5, 65.4, 64.1, 58.7,56.5, 56.3, 33.6, 29.1, 21.1.

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS,2R)-10-(2,2,2-trichloroethoxycarbonyl)-11-hydroxy-7-methoxy-2-oxyacetyl-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](9)

TEMPO (0.69 g, 4.42 mmol, 0.4 eq) and BAIB (15.7 g, 48.7 mmol, 4.4 eq)were added to a stirred solution of diol 8 (11.5 g, 11.1 mmol) in DCM(150 mL). The reaction mixture was allowed to stir for 2 h and dilutedwith DCM (400 mL), washed with saturated NaHSO₃ (500 mL), saturatedNaHCO₃ (500 mL), brine (200 mL) and dried (MgSO₄). Filtration andevaporation of the solvent afforded the crude product which was purifiedby flash column chromatography (99.9:0.1 v/v CHCl₃/MeOH then gradient to99.7:0.3 v/v CHCl₃/MeOH) to provide the product 9 as a light yellowglass (4.43 g, 39%): ¹H NMR (400 MHz, CDCl₃) δ 7.28 (s, 2H, H6), 6.84(s, 2H, H9), 5.68 (d, 2H, J=9.1 Hz, H11), 5.37-5.35 (m, 2H, H2), 5.18(d, 2H, J=12.0 Hz, Troc CH₂), 4.32-4.21 (m, 6H, OCH₂CH₂CH₂O, Troc CH₂),4.03 (dd, 2H, J=13.2, 2.6 Hz, H3), 3.92 (s, 6H, OCH₃×2), 3.39-3.69 (m,4H, H3 and H11), 2.39-2.35 (m, 6H, OCH₂CH₂CH₂O and H1), 2.03 (s, 6H,CH₃CO₂×2); ¹³C NMR (100.6 MHz, CDCl₃) δ 170.4 (CH₃CO₂), 167.4(C_(quat)), 154.3 (C_(quat)), 150.5 (C_(quat)), 149.1 (C_(quat)), 127.4(C_(quat)), 124.9 (C_(quat)), 114.1 (C9), 110.9 (C6), 95.0 (Troc CCl₃),87.5 (C11), 75.0 (Troc CH₂), 71.4 (C2), 65.5 (OCH₂CH₂CH₂O), 58.4 (C11a),56.1 (OCH₃), 51.1 (C3), 35.8 (C1), 29.1 (OCH₂CH₂CH₂O), 21.0 (CH₃CO₂); MS(ES), m/z (relative intensity) 1058 ([M+Na]^(+.), 100).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS,2R)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-oxyacetyl-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](10)

TBSOTf (2.70 mL, 3.10 g, 11.7 mmol, 3.0 eq) was added to a stirredsolution of bis-alcohol 9 (4.05 g, 3.91 mmol) and 2,6-lutidine (1.82 mL,1.68 g, 15.6 mmol, 4.0 eq) in DCM (50 mL). The reaction mixture wasallowed to stir for 2.5 h and diluted with DCM (150 mL), washed withsaturated CuSO₄ (2×100 mL), saturated NaHCO₃ (100 mL), brine (200 mL)and dried (MgSO₄). Filtration and evaporation of the solvent affordedthe crude product which was purified by flash column chromatography(99.9:0.1 v/v CHCl₃/MeOH) to provide the product 10 as a white glass(5.05 g, >100%): ¹H NMR (400 MHz, CDCl₃) δ 7.05 (s, 2H, H6), 6.52 (s,2H, H9), 5.53 (d, 2H, J=9.0 Hz, H11), 5.14 (br s, 2H, H2), 4.99 (d, 2H,J=12.0 Hz, Troc CH₂), 4.06-3.87 (m, 8H, OCH₂CH₂CH₂O, Troc CH₂ and H11a),3.71 (s, 6H, OCH₃×2), 3.48-3.43 (m, 4H, H3), 2.21-2.11 (m, 4H,OCH₂CH₂CH₂O and H1), 2.03-1.96 (m, 2H, H1), 1.81 (s, 6H, CH₃CO₂×2), 0.63(s, 18H, TBS CH₃×6), 0.00 (s×2, 12H, TBS CH₃×4); ¹³C NMR (100.6 MHz,CDCl₃) δ 170.3 (CH₃CO₂), 167.9 (C_(quat)), 153.6 (C_(quat)), 150.4(C_(quat)), 149.2 (C_(quat)), 127.9 (C_(quat)), 125.5 (C_(quat)), 113.9(C9), 110.7 (C6), 95.2 (Troc CCl₃), 88.2 (C11), 74.7 (Troc CH₂), 71.7(C2), 65.0 (OCH₂CH₂CH₂O), 60.5 (C11a), 56.1 (OCH₃), 51.2 (C3), 36.2(C1), 28.8 (OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 21.0 (CH₃CO₂), 17.8 (TBSC_(quat)), 14.2 and 14.1 (TBS CH₃); MS (ES), m/z (relative intensity)1285 ([M+21]^(+.), 100), 1265 ([M+H]^(+.), 75).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS,2R)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-hydroxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](11)

A solution of K₂CO₃ (93 mg, 0.67 mmol, 5.0 eq) in H₂O (2 mL) was addeddropwise to a stirred solution of acetate 10 (170 mg, 0.13 mmol) in MeOH(3 mL). The initial colorless solution eventually turned yellow and theformation of a white precipitate was observed. The reaction mixture wasallowed to stir for 16 h when TLC (95:5 v/v CHCl₃/MeOH) showed thecomplete consumption of the starting material. Excess solvent wasremoved by rotary evaporation and the mixture was carefully neutralizedwith 1N HCl to pH 7. The resulting mixture was extracted with EtOAc(3×25 mL) and the combined organic layers were then washed with brine(40 mL) and dried (MgSO₄). Filtration and removal of the solventafforded the product 11 as a white glass (151 mg, 95%): ¹H NMR (400 MHz,CDCl₃) δ 6.94 (s, 2H, H6), 6.52 (s, 2H, H9), 5.53 (d, 2H, J=9.0 Hz,H11), 5.00 (d, 2H, J=12.0 Hz, Troc CH₂), 4.36-4.35 (m, 2H, H2),4.06-3.82 (m, 8H, OCH₂CH₂CH₂O, Troc CH₂ and H3), 3.61 (s, 6H, OCH₃×2),3.54-3.48 (m, 2H, H11a), 3.39-3.34 (m, 2H, H3), 2.96 and 2.95 (br s×2,2H, OH×2), 2.21-2.20 (m, 2H, OCH₂CH₂CH₂O), 2.19-2.08 (m, 2H, H1),1.90-1.74 (m, 2H, H1), 0.64 (s, 18H, TBS CH₃×6), 0.00 (s, 12H, TBSCH₃×4); ¹³C NMR (100.6 MHz, CDCl₃) δ 168.5 (C_(quat)), 153.6 (C_(quat)),150.3 (C_(quat)), 149.1 (C_(quat)), 127.9 (C_(quat)), 125.4 (C_(quat)),113.9 (C9), 110.7 (C6), 95.2 (Troc CCl₃), 88.3 (C11), 74.7 (Troc CH₂),69.4 (C2), 65.0 (OCH₂CH₂CH₂O), 60.9 (C11a), 55.9 (OCH₃), 54.1 (C₃), 38.8(C1), 28.9 (OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 17.8 (TBS C_(quat)); MS (ES),m/z (relative intensity) 1196 ([M+16]^(+.), 100), 1181 ([M+H]^(+.), 82).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-oxo-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](12)

A solution of anhydrous DMSO (0.82 mL, 0.90 g, 11.5 mmol, 6.0 eg) in dryDCM (20 mL) was added dropwise to a stirred solution of oxalyl chloride(2.88 mL of a 2 M solution in DAM, 5.76 mmol, 3.0 eq) under a nitrogenatmosphere at −60° C. (liq N₂/CHCl₃). After stirring at −55° C. for 1.5h, a solution of the substrate 11 (2.26 g, 1.92 mmol) in dry DCM (30 mL)was added dropwise to the reaction mixture, which was then stirred for afurther 2 h at −45° C. A solution of TEA (10.8 mL, 7.82 g; 71.7 mmol,4.2 eq) in dry DCM (90 mL) was added dropwise to the mixture and stirredfor a further 30 min. The reaction mixture was left to warm to 0° C.,washed with cold 1 N HCl (2×50 mL), H₂O (50 mL), brine (50 mL) and dried(MgSO₄). Filtration and evaporation of the solvent in vacuo afforded thecrude product which was purified by flash column chromatography (70:30v/v hexane/EtOAc then gradient to 40:60 v/v hexane/EtOAc) to affordcarbinolamine 12 as a white glass (1.62 g, 72%): ¹H NMR (400 MHz, CDCl₃)δ 7.02 (s, 2H, H6), 6.54 (s, 2H, H9), 5.59 (d, 2H, J=9.2 Hz, H11), 4.98(d, 2H, J=12.0 Hz, Troc CH₂), 4.09-3.86 (m, 8H, OCH₂CH₂CH₂O, Troc CH₂and H3), 3.75-3.66 (m, 10H, OCH₃×2, H11a, and H3), 2.72 (dd, 2H, J=10.2,19.6 Hz, H1), 2.82 (dd, 2H, J=2.6, 19.6 Hz, H1), 2.22-2.19 (m, 2H,OCH₂CH₂CH₂O), 0.63 (s, 18H, TBS CH₃×6), 0.00 (s×2, 12H, TBS CH₃×4); ¹³CNMR (100.6 MHz, CDCl₃) δ 207.7 (C2), 168.0 (C_(quat)), 153.7 (C_(quat)),150.7 (C_(quat)), 149.4 (C_(quat)), 127.8 (C_(quat)), 124.6 (C_(quat)),114.0 (C9), 110.6 (C6), 95.1 (Troc CCl₃), 87.4 (C11), 74.8 (Troc CH₂),65.0 (OCH₂CH₂CH₂O), 58.9 (C11a), 56.1 (OCH₃), 53.0 (C3), 40.3 (C1), 28.8(OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 17.8 (TBS C_(quat)); MS (ES), m/z(relative intensity) 1224 ([M+48]^(+.), 100), 1210 ([M+34]^(+.), 60),1199 ([M+Na]^(+.), 35), 1192 ([M+16]^(+.), 40), 1176 (M^(+.), 18).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-[[(trifluoromethyl)sulfonyl]oxy]-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](13)

Anhydrous triflic anhydride (3.09 mL, 5.19 g, 18.4 mmol, 22 eq) takenfrom a freshly opened ampule was added rapidly in one portion to avigorously stirred solution of ketone 12 (0.98 g, 0.84 mmol) andanhydrous pyridine (1.49 mL, 1.46 g, 18.4 mmol, 22 eq) in dry DAM (50mL) at room temperature under a nitrogen atmosphere. The initialprecipitate dissolved gradually and the solution eventually turned adark red colour. The reaction mixture was allowed to stir for 4.5 h whenTLC (80:20 v/v EtOAc/hexane) revealed the complete consumption of thestarting material. The mixture was poured into cold saturated NaHCO₃ (60mL) and extracted with DCM (3×80 mL). The combined organic layers werethen washed with saturated CuSO₄ (2×125 mL), brine (125 mL) and dried(MgSO₄). Filtration and evaporation of the solvent afforded the crudeproduct which was purified by flash column chromatography (80:20 v/vhexane/EtOAc) to afford triflate 13 as a light yellow glass (0.74 mg,61%): [α]²⁵ _(D)=+46.0° (c=0.33, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.23(s, 2H, H6), 7.19 (s, 2H, H3), 6.77 (s, 2H, H9), 5.94 (d, 2H, J=8.9 Hz,H11), 5.23 (d, 2H, J=12.0 Hz, Troc CH₂), 4.31-4.28 (m, 2H, OCH₂CH₂CH₂O),4.18 (d, 2H, J=12.2 Hz, Troc CH₂), 4.15-4.13 (m, 2H, OCH₂CH₂CH₂O),3.95-3.91 (m, 8H, OCH₃×2, H11a), 3.35 (dd, 2H, J=11.0, 16.6 Hz, H1),2.84 (d, 2H, J=16.6 Hz, H1), 2.46-2.44 (m, 2H, OCH₂CH₂CH₂O), 0.89 (s,18H, TBS CH₃×6), 0.29 and 0.26 (s×2, 12H, TBS CH₃×4); ¹³C NMR (100.6MHz, CDCl₃) δ 164.9 (C_(quat)), 153.6 (C_(quat)), 151.0 (C_(quat)),149.5 (C_(quat)), 136.0 (C_(quat)), 127.7 (C_(quat)), 123.9 (C_(quat)),121.0 (C3), 114.0 (C9), 110.9 (C6), 95.1 (Troc CCl₃), 86.3 (C11), 74.8(Troc CH₂), 65.0 (OCH₂CH₂CH₂O), 60.6 (C11a), 56.2 (OCH₃), 34.4 (C1),28.8 (OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 17.8 (TBS C_(quat)); IR (CHCl₃)3020, 2957, 2860, 1725, 1674, 1651, 1604, 1516, 1466, 1454, 1431, 1409,1329, 1312, 1274, 1216, 1138, 1113, 1083, 1042, 1006, 900, 840, 757,668, 646, 610 cm⁻¹; MS (ES), m/z (relative intensity) 1461 ([M+21]^(+.),100), 1440 (M^(+.), 55).

Example 21,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-[(N,N-dimethylaminocarbonyl)vinyl]-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-204)1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-[(N,N-dimethylaminocarbonyl)vinyl]-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](14)

A mixture of triflate 13 (732 mg, 1.22 mmol), N,N-dimethylacrylamide(0.14 mL, 134 mg, 1.35 mmol, 5.0 eq), DABCO (152 mg, 1.35 mmol, 5.0 eq),(CH₃CN)₂PdCl₂ (14 mg, 0.05 mmol, 0.2 eq) and MeOH (15 mL) was stirred at55-65° C. for 16 h. The reaction was worked-up by pouring the mixtureinto CHCl₃ (20 mL) and aqueous NaHCO₃ (20 mL). The aqueous layer wasextracted with CHCl₃ (3×20 mL) and the CHCl₃ extracts were combined,washed with H₂O (50 mL), brine (50 mL) and dried (MgSO₄). Filtration andevaporation of solvent gave the crude product as a dark brown glass. Theresidue was purified by flash column chromatography (99.9:0.1 v/vCHCl₃/MeOH then gradient to 99.2:0.8 v/v CHCl₃/MeOH) to give the coupledproduct 14 as a light yellow glass (80 mg, 22%): [α]²⁶ _(D)=+87.2°(c=0.11, CHCl₃); ¹H NMR (250 MHz, CDCl₃) δ 7.51 (d, 2H, J=15.0 Hz, H12),7.32 (s, 2H, H3), 7.28 (s, 2H, H6), 6.79 (s, 2H, H9), 6.10 (d, 2H,J=15.0 Hz, H13), 5.88 (d, 2H, J=8.8 Hz, H11), 5.23 (d, 2H, J=12.0 Hz,Troc CH₂), 4.33-4.28 (m, 2H, OCH₂CH₂CH₂O), 4.18 (d, 1H, J=12.2 Hz, TrocCH₂), 4.18-4.14 (m, 2H, OCH₂CH₂CH₂O), 3.98-3.95 (m, 8H, H11a andOCH₃×2), 3.17-3.06 (m, 8H, H1 and NCH₃×2), 2.65 (d, 1H, J=16.2 Hz, H1),2.47-2.44 (m, 2H, OCH₂CH₂CH₂O), 0.92 (s, 18H, TBS CH₃×6), 0.29 and 0.27(s×2, 12H, TBS CH₃×4); ¹³C NMR (62.9 MHz, CDCl₃) δ 166.5 (CONMe₂), 132.5(C12), 132.6 (C3), 116.8 (C13), 114.0 (C9), 110.8 (C6), 95.2 (TrocCCl₃), 86.9 (C11), 74.8 (Troc CH₂), 65.0 (OCH₂CH₂CH₂O), 61.9 (C11a),56.2 (OCH₃), 33.5 (C1), 28.8 (OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 17.9 (TBSC_(quat)); MS (ES), m/z (relative intensity) 1337 ([M−H]^(+.), 100),1327 (27), 1316 (34).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-[(N,N-dimethylaminocarbonyl)vinyl]-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-204)

10% Cd/Pd couple (120 mg, 0.99 mmol, 16.5 eq) was added to a rapidlystirring mixture of 14 (79 mg, 0.06 mmol), THF (1.5 mL) and 1 N NH₄OAc(1.5 mL). The reaction mixture was allowed to stir for 3.5 h. The solidswere filtered and rinsed with H₂O and CHCl₃. The aqueous layer wasextracted with CHCl₃ (3×20 mL), and the organic extracts were combined,washed with brine (50 mL) and dried (MgSO₄). Filtration and evaporationof solvent left a yellow solid which was purified by flash columnchromatography (99.9:0.1 v/v CHCl₃/MeOH then gradient to 95:5 v/vCHCl₃/MeOH) to afford ZC-204 as a yellow glass (13.4 mg, 31%): [α]²⁵_(D)=+235.7° (c=0.07, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, 2H,J=3.9 Hz, H11), 7.54 (d, 2H, J=15.1 Hz, H12), 7.51 (s, 2H, H3), 7.34 (s,2H, H6), 6.88 (s, 2H, H9), 6.18 (d, 2H, J=15.0 Hz, H13), 4.43-4.27 (m,6H, OCH₂CH₂CH₂O and H11a), 3.95 (s, 6H, OCH₃×2), 3.41-3.34 (m, 2H, H1),3.23-3.04 (m, 14H, H1 and NCH₃×4), 2.47-2.44 (m, 2H, OCH₂CH₂CH₂O); ¹³CNMR (62.9 MHz, CDCl₃) δ 166.4 (CONMe₂), 162.1 (C11), 161.7 (C_(quat)),151.5 (C_(quat)), 148.2 (C_(quat)), 140.4 (C_(quat)), 135.2 (C12), 132.2(C3), 121.8 (C_(quat)), 118.6 (C_(quat)), 117.0 (C13), 112.0 (C9), 111.3(C6), 65.4 (OCH₂CH₂CH₂O), 56.2 (OCH₃), 54.2 (C11a), 37.4 and 35.9(NCH₃), 33.8 (C1)_(28.8) (OCH₂CH₂CH₂O); MS (ES), m/z (relativeintensity) 741 ([M+H₂O]^(+.), 25), 723 (M^(+.), 62).

Example 31,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-(p-methoxybenzene)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-207)1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-(p-methoxybenzene)-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](15)

A solution of TEA (0.20 mL, 148 mg, 1.46 mmol, 6.0 eq) in H₂O (1.5 mL)and EtOH (10 mL) was added to a solution of triflate 13 (350 mg, 0.24mmol) in toluene (10 mL) at room temperature. To this mixture4-methoxybenzeneboronic acid (96 mg, 0.63 mmol, 2.6 eq) and Pd(PPh₃)₄(11 mg, 9 μmol, 0.04 eq) were added. The reaction mixture was allowed tostir for 15 min when TLC (80:20 v/v EtOAc/hexane) revealed the completeconsumption of the starting material. Excess solvent was removed and theresidue was dissolved in EtOAc (25 mL), washed with H₂O (15 mL), brine(15 mL) and dried (MgSO₄). Filtration and evaporation of solventafforded the crude product which was purified by flash columnchromatography (80:20 v/v hexane/EtOAc then gradient to 50:50 v/vhexane/EtOAc) to afford 15 as a yellow glass (286 mg, 87%): ¹H NMR (400MHz, CDCl₃) δ 7.38 (s, 2H, H3), 7.32-7.28 (m, 6H, H6 and H13), 6.92 (d,4H, J=8.7 Hz, H14), 6.81 (s, 2H, H9), 5.93 (d, 2H, J=8.8 Hz, H11), 5.24(d, 2H, J=12.0 Hz, Troc CH₂), 4.34-4.29 (m, 2H, OCH₂CH₂CH₂O), 4.20-4.11(m, 4H, Troc CH₂ and OCH₂CH₂CH₂O), 4.00-3.96 (m, 8H, H11a and OCH₃×2),3.84 (s, 6H, OCH₃×2), 3.36 (dd, 2H, J=10.8, 16.6 Hz, H1), 2.85 (d, 2H,J=16.5 Hz, H1), 2.48-2.45 (m, 2H, OCH₂CH₂CH₂O), 0.93 (s, 18H, TBSCH₃×6), 0.30 and 0.27 (s×2, 12H, TBS CH₃×4); ¹³C NMR (100.6 MHz, CDCl₃)δ 162.5 (C_(quat)), 161.3 (C_(quat)), 159.2 (C_(quat)), 151.1(C_(quat)), 148.1 (C_(quat)), 140.3 (C_(quat)), 126.2 (C13), 126.0(C_(quat)), 123.2 (C_(quat)), 121.9 (C3), 119.3 (C_(quat)), 114.3 (C6),111.9 (C14), 111.2 (C9), 95.2 (Troc CCl₃), 87.3 (C11), 74.8 (Troc CH₂),65.0 (OCH₂CH₂CH₂O), 61.5 (C11a), 56.1 and 55.3 (OCH₃), 35.3 (C1), 28.8(OCH₂CH₂CH₂O), 25.7 (TBS CH₃), 17.9 (TBS C_(quat)); MS (ES), m/z(relative intensity) 1357 (M^(+.), 63), 1114 (48), 955 (59), 919 (78).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-(p-methoxybenzene)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-207)

10% Cd/Pd couple (461 mg, 3.73 mmol, 20 eq) was added to a rapidlystirring mixture of 15 (253 mg, 0.19 mmol), THF (5 mL) and 1 N NH₄OAc (5mL). The reaction mixture was allowed to stir for 1.5 h when TLC showedthe complete consumption of the starting material. The solids werefiltered and rinsed with H₂O and DAM. The aqueous layer was extractedwith DCM (3×30 mL) and the organic extracts were combined, washed withbrine (50 mL) and dried (MgSO₄). Filtration and evaporation of solventafforded the crude product which was purified by flash columnchromatography (99.9:0.1 v/v CHCl₃/MeOH then gradient to 95:5 v/vCHCl₃/MeOH) to afford ZC-207 as a yellow glass (132 mg, 96%): [α]²⁰_(D)=+880.0° (c=0.22, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, 2H,J=3.9 Hz, H11), 7.44 (s, 2H, H6), 7.30 (s, 2H, H3), 7.24 (d, 4H, J=8.7Hz, H13), 6.81 (d, 4H, J=8.7 Hz, H14), 6.79 (s, 2H, H9), 4.30-4.18 (m,6H, OCH₂CH₂CH₂O and H11a), 3.86 (s, 6H, OCH₃×2), 3.74 (s, 6H, OCH₃×2),3.48 (dd, 2H, J=11.8, 16.2 Hz, H1), 2.85 (d, 2H, J=16.2 Hz, H1),2.38-2.32 (m, 2H, OCH₂CH₂CH₂O); ¹³C NMR (62.9 MHz, CDCl₃) δ 162.5 (C11),161.3 (C_(quat)), 159.2 (C_(quat)), 151.1 (C_(quat)), 148.1 (C_(quat)),140.3 (C_(quat)), 126.2 (C13), 126.0 (C_(quat)), 123.2 (C_(quat)), 121.9(C3), 114.3 (C14), 111.9 (C9), 111.2 (C6), 65.4 (OCH₂CH₂CH₂O), 56.2 and55.3 (OCH₃), 53.8 (C11a), 35.6 (C1), 28.9 (OCH₂CH₂CH₂O); MS (ES), m/z(relative intensity) 741 (M^(+.), 43), 660 (71).

Example 41,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-(1-propenyl)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-211)1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-(1-propenyl)-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](16)

A solution of TEA (0.11 mL, 81 mg, 0.80 mmol, 6.0 eq) in H₂O (3 mL) andEtOH (10 mL) was added to a solution of triflate 13 (192 mg, 0.13 mmol)in toluene (5 mL) at room temperature. To this mixturetrans-propenylboronic acid (30 mg, 0.35 mmol, 2.6 eq) and Pd(PPh₃)₄ (6mg, 5 μmol, 0.04 eq) were added. The reaction mixture was heated at 76°C. for 2 h when TLC (50:50 v/v EtOAc/hexane) revealed the completeconsumption of the starting material. Excess solvent was removed and theresidue was dissolved in EtOAc (15 mL), washed with H₂O (10 mL), brine(10 mL) and dried (MgSO₄). Filtration and evaporation of solventafforded the crude product which was purified by flash columnchromatography (80:20 v/v hexane/EtOAc) to afford 16 as a light yellowglass (40 mg, 25%): [α]²⁰ _(D)=+75.0° (c=0.20, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.28 (s, 2H, H6), 6.90 (s, 2H, H3), 6.78 (s, 2H, H9), 6.26 (d,2H, J=14.8 Hz, H12), 5.85 (d, 2H, J=8.8 Hz, H11), 5.54 (d, J=6.8, 15.4Hz, 2H, H13), 5.23 (d, 2H, J=12.0 Hz, Troc CH₂), 4.32-4.26 (m, 2H,OCH₂CH₂CH₂O), 4.18-4.11 (m, 4H, Troc CH₂ and OCH₂CH₂CH₂O), 3.94 (s, 6H,OCH₃×2), 3.89-3.83 (m, 2H, H11a), 3.07 (dd, 2H, J=10.6, 15.9 Hz, H1),2.60 (d, 2H, J=16.3 Hz, H1), 2.46-2.43 (m, 2H, OCH₂CH₂CH₂O), 1.85 (d,6H, J=6.6 Hz, H14), 0.90 (s, 18H, TBS CH₃×6), 0.28 and 0.25 (s×2, 12H,TBS CH₃×4); ¹³C NMR (100.6 MHz, CDCl₃) δ 163.6 (C_(quat)), 153.6(C_(quat)), 150.4 (C_(quat)), 149.2 (C_(quat)), 127.7 (C_(quat)), 126.4(C13), 125.6 (C_(quat)), 124.7 (C12 and C3), 123.5 (C_(quat)), 114.0(C9), 110.7 (C6), 95.2 (Troc CCl₃), 87.2 (C11), 74.7 (Troc CH₂), 65.0(OCH₂CH₂CH₂O), 61.4 (C11a), 56.1 (OCH₃), 33.9 (C1), 28.8 (OCH₂CH₂CH₂O),25.6 (TBS CH₃), 18.4 (C14), 17.9 (TBS C_(qaut)); MS (ES), m/z (relativeintensity) 1246 ([M+22]^(+.), 100), 1226 ([M+2]^(+.), 88).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-(1-propenyl)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-211)

10% Cd/Pd couple (81 mg, 0.65 mmol, 20 eq) was added to a rapidlystirring mixture of 16 (40 mg, 0.03 mmol), THF (1 mL) and 1 N NH₄OAc (1mL). The reaction mixture was allowed to stir for 1 h when TLC showedthe complete consumption of the starting material. The solids werefiltered and rinsed with H₂O and CHCl₃. The aqueous layer was extractedwith CHCl₃ (3×5 mL) and the organic extracts were combined, washed withH₂O (10 mL), brine (10 mL) and dried (MgSO₄). Filtration and evaporationof solvent afforded the crude product which was purified by flash columnchromatography (99.8:0.2 v/v CHCl₃/MeOH then gradient to 97:3 v/vCHCl₃/MeOH) to afford ZC-211 as a yellow glass (14.7 mg, 74%): [α]²⁰_(D)=+1102.0° (c=0.15, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, 2H,J=3.8 Hz, H11), 7.42 (s, 2H, H6), 6.84 (s, 2H, H3), 6.77 (s, 2H, H9),6.19 (d, 2H, J=15.5 Hz, H12), 5.52 (dd, J=6.8, 15.4 Hz, 2H, H13),4.27-4.16 (m, 6H, OCH₂CH₂CH₂O and H11a), 3.84 (s, 6H, OCH₃×2), 3.22 (dd,2H, J=11.5, 16.1 Hz, H1), 3.03 (dd, 2H, J=4.8, 16.2 Hz, H1), 2.38-2.32(m, 2H, OCH₂CH₂CH₂O), 1.77 (d, 6H, J=6.6 Hz, H14); ¹³C NMR (100.6 MHz,CDCl₃) δ 162.6 (C11), 161.2 (C_(quat)), 151.1 (C_(quat)), 148.1(C_(quat)), 140.3 (C_(quat)), 127.7 (C_(quat)), 126.9 (C13), 124.4 (C12and C3), 123.9 (C_(quat)), 119.3 (C_(quat)), 111.9 (C6), 111.2 (C9),65.4 (OCH₂CH₂CH₂O), 56.2 (OCH₃), 53.8 (C11a), 34.2 (C1), 28.8(OCH₂CH₂CH₂O), 18.5 (C14); MS (ES), m/z (relative intensity) 609(M^(+.), 100).

Example 51,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-ethynylphenyl-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-209)1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(2,2,2-trichloroethoxycarbonyl)-11-(tert-butyldimethylsilyloxy)-7-methoxy-2-ethynylphenyl-1,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]](17)

A catalytic amount of Pd(PPh₃)₄ was added to a stirred mixture oftriflate 13 (193 mg, 0.13 mmol), LiCl (34 mg, 0.80 mmol, 6.0 eq) andtributyl(phenylethynyl)tin (0.14 mL, 157 mg, 0.40 mmol, 3.0 eq) in dryTHF (5 mL). The reaction mixture was heated at reflux for 2.5 h when TLCshowed the complete consumption of the starting material. After coolingto room temperature, excess solvent was removed and the residue wasdissolved in DCM (20 mL), followed by washing with 10% NH₄OH (20 mL).The aqueous layer was extracted with DCM (3×20 mL), and the organicextracts were combined, washed with brine (50 mL) and dried (MgSO₄).Filtration and evaporation of solvent afforded the crude product whichwas purified by flash column chromatography (80:20 v/v hexane/EtOAc) toafford 17 as a yellow glass (162 mg, 90%): ¹H NMR (400 MHz, CDCl₃) δ7.40-7.37 (m, 4H, H15), 7.26-7.19 (m, 10H, H3, H6, H16 and H17), 6.70(s, 2H, H9), 5.85 (d, 2H, J=8.8 Hz, H11), 5.15 (d, 2H, J=12.0 Hz, TrocCH₂), 4.24-4.19 (m, 2H, OCH₂CH₂CH₂O), 4.12-4.02 (m, 4H, Troc CH₂ andOCH₂CH₂CH₂O), 3.86-3.79 (m, 8H, OCH₃×2 and H11a), 3.15 (dd, 2H, J=10.8,16.5 Hz, H1), 2.63 (d, 2H, J=16.5 Hz, H1), 2.37-2.35 (m, 2H,OCH₂CH₂CH₂O), 0.82 (s, 18H, TBS CH₃×6), 0.22 and 0.18 (s×2, 12H, TBSCH₃×4); ¹³C NMR (100.6 MHz, CDCl₃) δ 163.8 (C_(quat)), 153.6 (C_(quat)),150.8 (C_(quat)), 149.3 (C_(quat)), 133.3 (C3), 131.4 (C15), 128.4 (C16and C17), 127.8 (C_(quat)), 125.1 (C_(quat)), 123.0 (C_(quat)), 114.0(C6), 110.0 (C9), 104.8 (C_(quat)), 95.2 (Troc CCl₃), 93.7 (C_(alkyne)),86.9 (C11), 83.6 (C_(alkyne)), 74.8 (Troc CH₂), 66.0 (OCH₂CH₂CH₂O), 61.4(C11a), 56.2 (OCH₃), 37.8 (C1), 28.8 (OCH₂CH₂CH₂O), 25.6 (TBS CH₃), 17.8(TBS C_(quat)); MS (ES), m/z (relative intensity) 1344 (M^(+.), 8), 625(100).

1,1′-[[(Propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-ethynylphenyl-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one]](ZC-209)

10% Cd/Pd couple (314 mg, 2.55 mmol, 20 eq) was added to a rapidlystirring mixture of 17 (162 mg, 0.13 mmol), THF (4 mL) and 1 N NH₄OAc (4mL). The reaction mixture was allowed to stir for 45 min when TLC showedthe complete consumption of the starting material. The solids werefiltered and rinsed with H₂O and CHCl₃. The aqueous layer was extractedwith CHCl₃ (3×25 mL) and the organic extracts were combined, washed withH₂O (50 mL), brine (50 mL) and dried (MgSO₄). Filtration and evaporationof solvent afforded the crude product which was purified by flash columnchromatography (99.8:0.2 v/v CHCl₃/MeOH then gradient to 97.5:2.5 v/vCHCl₃/MeOH) to afford ZC-209 as a yellow glass (33 mg, 38%): ¹H NMR (400MHz, CDCl₃) δ 7.79 (d, 2H, J=3.9 Hz, H11), 7.42 (s, 2H, H6), 7.39-7.37(m, 4H, H15), 7.26-7.19 (m, 8H, H3, H16 and H17), 6.78 (s, 2H, H9),4.30-4.19 (m, 6H, OCH₂CH₂CH₂O and H11a), 3.86 (s, 6H, OCH₃×2), 3.36 (dd,2H, J=11.7, 16.4 Hz, H1), 3.18 (dd, 2H, J=5.4, 16.4 Hz, H1), 2.37-2.34(m, 2H, OCH₂CH₂CH₂O); ¹³C NMR (100.6 MHz, CDCl₃) δ 162.0 (C11), 161.3(C_(quat)), 151.4 (C_(quat)), 148.2 (C_(quat)), 140.3 (C_(quat)), 132.8(C3), 131.4 (C15), 128.4 (C16 and C17), 122.9 (C_(quat)), 118.7(C_(quat)), 112.0 (C6), 111.2 (C9), 105.1 (C_(quat)), 94.3 (C_(alkyne)),83.3 (C_(alkyne)), 65.5 (OCH₂CH₂CH₂O), 56.2 (OCH₃), 53.8 (C11a), 37.9(C1), 28.8 (OCH₂CH₂CH₂O); MS (ES), m/z (relative intensity) 729 (M^(+.),100).

Example 6 Formation of Key Monomer Intermediate((11S,11aS)-7,8-Dimethoxy-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-2-[[(trifluoromethyl)sulfonyl]oxy]-1,2,3,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(27))(2S)(4R)-N-(4,5-Dimethoxy-2-nitrobenzoyl)-2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine(19)

A stirred solution of 6-nitroveratric acid (18) (1.49 g, 6.58 mmol; 1.2Equiv.) in dry DMF (2 mL) and DCM (80 mL) was treated withN-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (1.26 g,6.58 mmol, 1.2 Equiv.) and cooled to 0° C. 1-Hydroxybenzotriazolehydrate (1.03 g, 6.58 mmol, 1.2 Equiv.) was added in portions and thereaction mixture was allowed to warm to room temperature. After stirringfor 1 h, a solution of 3 (1.5 g, 5.48 mmol, 1.0 Equiv.) in DCM (80 mL)was added dropwise and the mixture stirred for a further 15 h. This wasfollowed by heating at 55° C. for a further 3 h. The reaction mixturewas washed with NH₄Cl (60 mL), NaHCO₃ (60 mL), brine (60 mL), dried(MgSO₄) and concentrated in vacuo. Purification by flash chromatography(EtOAc/petroleum ether 4:6) afforded the product 19 as pale crystals(2.11 g, 79.9%): m.p. 134° C.; [α]_(D) ¹⁹=−91.9° (c=0.408, CHCl₃); ¹HNMR (CDCl₃, 400 MHz) δ 0.12 (s, 6H, Si(CH₃)₂), 0.93 (s, 9H, C(CH₃)₃),2.04 (s, 3 H, C═OCH₃), 2.20-2.28 (m, 1H, H1a), 2.39-2.45 (m, 1H, H1b),3.22 (d, 1H, J=11.74 Hz, H3a), 3.47 (dd, 1H, J=11.89, 4.70 Hz, H3b),3.75 (d, 1H, J=8.39 Hz, H11), 3.94 (s, 3H, CH₃O7), 3.98 (s, 3H, CH₃O8),4.21 (d, 1H, J=9.76 Hz, H11), 4.56 (m, 1 H, H11a), 5.19 (m, 1H, H2b),6.73 (s, 1H, H6), 7.68 (s, 1H, H9); ¹³C NMR (CDCl₃, 100 MHz) δ 171.0(C═O), 166.3 (C5), 154.0 (C7), 149.1 (C8), 137.6 (C5-6), 127.8 (C9-10),109.1 (C6), 107.3 (C9), 72.9 (C2), 62.6 (C11), 57.4 (C11a), 56.5, 56.6(CH₃O7 and CH₃O8), 52.0 (C3), 33.0 (C1), 25.7 (C(CH₃)₃), 21.2 (C═OCH₃),18.1 (Cquat), −5.5 (SiCH₃)₂); IR (film) 2953, 2856, 1740 (C═O), 1648(C═O), 1579, 1525, 1463, 1427, 1338, 1278, 1243, 1225, 1115, 1070, 1028,1004, 837, 780 cm⁻¹; MS (EI) m/z (relative intensity) 483 ([M+H]^(+.),100); Elem. Anal. calculated for C₂₂H₃₄N₂O₈Si: C, 54.75; H, 7.10; N,5.80. Found: C, 54.50; H, 7.08; N, 5.79.

(2S,4R)-N-(2-Amino-4,5-dimethoxybenzoyl)-2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine(20)

A suspension of 19 (61.75 g, 127.9 mmol; 1 Equiv.) and 10% w/w Pd/C(6.17 g) in ethanol (400 mL) was agitated under a H₂ atmosphere (45 psi)using Parr apparatus over a period of 3 h. The suspension was filteredthrough celite and the filtrate was evaporated in vacuo to afford 20 asa pale yellow oil (57.5 g, 99%): [α]_(D) ¹⁹=−105.1° (c=0.490, CHCl₃); ¹HNMR (CDCl₃, 400 MHz) δ 0.03 (s, 6H, Si(CH₃)₂), 0.88 (s, 9H, C(CH₃)₃),1.98 (s, 3H, C═OCH₃), 2.09-2.15 (m, 1H, H1a), 2.32-2.39 (m, 1H, H11b),3.57-3.64 (m, 2H, H3a and H11), 3.73-3.77 (m, 4H, H3b and CH₃O8), 3.82(s, 3H, CH₃O7), 4.00-4.11 (m (br), 1H, H11), 4.40-4.60 (m, 1H, H11a),5.21-5.27 (m, 1H, H2b), 6.21 (s, 1H, H9), 6.69 (s, 1H, H6); ¹³C NMR(CDCl₃, 100 MHz) δ 170.6 (C═O), 170.0 (C5), 151.9 (C7), 141.7 (C9-10),140.9 (C8), 112.2 (C6), 110.9 (C5-6), 100.6 (C9), 73.5 (C2), 62.6 (C11),57.0 (C11a), 55.8, (CH₃O7), 56.6 (CH₃O8), 56.3 (C3), 32.9 (C1), 25.8(C(CH₃)₃), 21.1 (C═OCH₃), 18.1 (Cquat), −5.5 (SiCH₃)₂); IR (film) 3455,3355 (NH₂), 2931, 2857, 1740 (C═O), 1628 (C═O), 1594, 1516, 1401, 1238,1165, 1120, 1006, 837, 778, 668 cm⁻¹; MS (EI) m/z (relative intensity)453 ([M+H]^(+.), 100).

(2S,4R)-N-(4,5-Dimethoxy-2-(2,2,2-trichloroethoxycarbonylamino)-benzoyl)-2-(tert-butyldimethylsilyloxymethyl)-4-oxyacetylpyrrolidine(21)

2,2,2-Trichloroethyl chloroformate (1.61 mL, 11.68 mmol, 2.2 Equiv.) wasadded to a stirred solution of 20 (2.40 g, 5.31 mmol; 1.0 Equiv.) andpyridine (1.72 mL, 21.24 mmol, 4.0 Equiv.) in dry DAM (70 mL) at −20° C.The mixture was allowed to warm to room temperature and stirred for afurther 2.5 h. The reaction mixture was washed with NH₄Cl (2×60 mL),CuSO₄ (60 mL), water (60 mL), brine (60 mL), dried (MgSO₄), filtered andconcentrated in vacuo to afford 21 as a colourless oil (3.32 g, 99%):[α]_(D) ²⁰=−43.4° (c=0.980, CHCl₃); ¹H NMR (CDCl₃, 400 MHz) δ 0.28 (s,6H, Si(CH₃)₂), 0.87 (s, 9H, C(CH₃)₃), 1.96 (s, 3H, C═OCH₃), 2.10-2.16(m, 1H, H1a), 2.35-2.41 (m, 1H, H1b), 3.55-3.65 (br m, 1H, H3a),3.68-3.74 (m, 2H, H11 and H3b), 3.78 (s, 3H, CH₃O7), 3.91 (s, 3H,CH₃O8), 4.06-4.10 (m, 2H, Cl₃CCH₂ rotamers and H11), 4.55-4.65 (m, 1H,H11a), 4.74-4.82 (m, 1H, Cl₃CCH₂, rotamers), 5.20-5.25 (m, 1H, H2b),6.75 (s, 1H, H6), 7.82 (br s, 1H, H9), 9.38 (br s, 1H, NH); ¹³C NMR(CDCl₃, 100 MHz) δ 170.5 (C═O), 169.2 (C5), 153.1, 151.4 (OC═ONH,rotamers), 151.9 (C8), 144.1 (C7), 132.2 (C5-6), 114.8 (C9-10), 111.1(C6), 104.3 (C9), 95.3, 93.9 (Cl₃C, rotamers), 77.3, 76.3 (Cl₃CCH₂,rotamers), 73.4 (C2), 62.3 (C11), 57.3 (C11a), 57.2 (C3), 56.1, 56.2(CH₃O7 and CH₃O8), 32.5 (C1), 25.8 (C(CH₃)₃), 21.1 (C═OCH₃), 18.1(Cquat), −5.5 (SiCH₃)₂); IR (film) 3318, 2954, 2858, 1774, 1743 (C═O andOC═ON), 1601 (NC═O), 1525, 1464, 1422, 1398, 1230, 1200, 1125, 1004,836, 777, 720 cm⁻¹; MS (EI) m/z (relative intensity) 629 ([M+H]^(+.),100).

(2S,4R)-N-(4,5-Dimethoxy-2-(2,2,2-trichloroethoxycarbonylamino)-benzoyl)-2-hydroxymethyl-4-oxyacetylpyrrolidine(22)

A mixture of acetic acid (81 mL) and water (18 mL) was added to astirred solution of 21 (5.10 g, 8.12 mmol; 1.0 Equiv.) in THF (45 mL).The resulting solution was stirred at room temperature for a period of48 h. The THF was removed in vacuo and the resulting mixture wasneutralised to pH 7 with solid NaHCO₃ (Caution! vigorous effervescence).The resulting aqueous layer was extracted with DCM (5×150 mL), dried(MgSO₄) and concentrated in vacuo. The oily residue was subjected toflash chromatography (EtOAc/Petroleum ether 6:4) to give 22 as a foam(4.16 g, 99%): [α]_(D) ¹⁸=−65.0° (c=0.500, CHCl₃); ¹H NMR (CDCl₃, 400MHz) δ 2.01 (s, 3H, C═OCH₃), 2.05-2.13 (m, 1H, H1b), 2.27 (dd, 1H,J=14.20, 7.62 Hz, H1a), 3.62 (d, 1H, J=12.36 Hz, H3a), 3.65-3.74 (m, 1H,H11), 3.76 (dd, 1H, J=12.57, 3.80 Hz, H3b), 3.85 (s, 3 H, CH₃O7), 3.93(s, 3H, CH₃O8), 3.98-4.08 (m, 1H, H11), 4.55-4.65 (m, 1H, H11a), 4.79(d, 1H, J=12.09 Hz, Cl₃CCH₂), 4.84 (d, 1H, J=12.04 Hz, Cl₃CCH₂),5.18-5.25 (m, 1H, H2b), 6.80 (s, 1H, H6), 7.73 (br s, 1H, H9), 9.03 (brs, 1H, NH); ¹³C NMR (CDCl₃, 100 MHz) δ 170.6 (C═O), 170.4 (C5), 152.1(OC═ONH), 151.5 (C8), 144.6 (C7), 131.2 (C5-6), 115.5 (C9-10), 110.8(C6), 104.8 (C9), 95.3 (Cl₃C), 74.4 (Cl₃CCH₂), 72.5 (C2), 64.5 (C11),58.8 (C11a), 56.6 (C3), 56.5 (CH₃O7), 56.1 (CH₃O8), 33.7 (C1), 21.1(C═OCH₃); IR (film) 3358 (br NH and OH), 3015, 2941, 1740 (C═O andOC═ON), 1602 (NC═O), 1525, 1463, 1433, 1398, 1231, 1174, 1125, 1037,969, 817, 756 cm⁻¹; MS (EI) m/z (relative intensity) 363([M−Cl₃CCH₂O]^(+.), 100), 513 ([M+H]^(+.), 95).

(11S,11aS,2R)-7,8-Dimethoxy-11-hydroxy-2-oxyacetyl-10-(2,2,2-trichloroethoxycarbonyl)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(23)

Diodobenzene diacetate (83.7 g, 259.8 mmol, 1.78 Equiv.) and2,2,6,6-tetramethylpiperidine nitroxyl (TEMPO) (4.50 g, 28.8 mmol, 0.2Equiv.) were added to a stirred solution of 22 (74.7 g, 145.4 mmol; 1.0Equiv.) in dry DCM (1.5 L). The reaction mixture was stirred at roomtemperature for 15 h and diluted with DCM (500 mL). The organic phasewas washed with a said sodium bisulphite (700 mL) and the aqueous layerwas back-extracted with DCM (3×200 mL). The organic layers werecombined, dried (MgSO₄), filtered and concentrated in vacuo.Purification by flash chromatography (EtOAc/Petroleum ether 7:3)afforded 23 as a white glass (57.65 g, 77%): [α]_(D) ¹⁸=+99.4° (c=0.483,CHCl₃); ¹H NMR (CDCl₃, 400 MHz) δ 2.04 (s, 3H, C═OCH₃), 2.34-2.46 (m,2H, H1b and H1a), 3.69-3.77 (m, 2H, H3b and 11a), 3.92 (s, 3H, CH₃O8),3.95 (s, 3H, CH₃O7), 4.05 (dd, 1H, J=13.13, 2.35 Hz, H3a), 4.23 (d, 1H,J=12.02 Hz, Cl₃CCH₂), 5.25 (d, 1H, J=12.02 Hz, Cl₃CCH₂), 5.38 (p, 1 H,J=4.10 Hz, H2b), 5.70 (dd, 1H, J=9.66, 3.79 Hz, H11), 6.81 (s, 1H, H9),7.27 (s, 1H, H6); ¹³C NMR (CDCl₃, 100 MHz) δ 170.3 (C═O), 167.4 (C5),154.4 (OC═ONH), 151.1 (C8), 148.8 (C7), 127.5 (C9-10), 124.7 (C5-6),112.7 (C9), 110.7 (C6), 95.0 (Cl₃C), 87.6 (C11), 75.0 (Cl₃CCH₂), 71.4(C2), 58.3 (C11a), 56.19, 56.13 (CH₃O8 and CH₃O7), 51.1 (C3), 35.9 (C1),21.0 (C═OCH₃); IR (film) 3421 (br OH), 3008, 2946, 1719 (C═O), 1623(OC═ON), 1603 (NC═O), 1515, 1429, 1374, 1304, 1238, 1212, 1057, 870,819, 758, 711, 644 cm⁻¹; MS (EI) m/z (relative intensity) 511([M−H]^(+.), 100), 512.5 ([M+H]^(+.), 99).

(17S,11aS,2R)-7,8-Dimethoxy-2-oxyacetyl-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(24)

TBDMSOTf (0.56 mL, 2.44 mmol; 1.5 Equiv.) was added to a stirredsolution of 23 (834 mg, 1.63 mmol, 1.0 Equiv.) and 2,6-lutidine (0.38mL, 3.26 mmol, 2.0 Equiv.) in dry DCM (5 mL). The mixture was stirred atroom temperature for 30 min and diluted with DCM (20 mL). The mixturewas washed with sat^(d) CuSO₄ (2×20 mL), sat^(d) NaHCO₃ (30 mL), brine(30 mL), dried (MgSO₄) and concentrated in vacuo to afford 6 as whiteglass (1.01 g, 99%): [α]_(D) ¹⁸=+52.7° (c=0.237, CHCl₃); ¹H NMR (CDCl₃,400 MHz) δ 0.23 (s, 6H, Si(CH₃)₂), 0.87 (s, 9H, C(CH₃)₃), 2.03 (s, 3H,C═OCH₃), 2.18-2.25 (m, 1H. H1b), 2.30-2.40 (m, 1H, H1a), 3.66-3.72 (m,2H, H3b and 11a), 3.89 (s, 3H, CH₃O8), 3.95 (s, 3H, CH₃O7), 4.13 (d, 1H,J=13.40 Hz, H3a), 4.18 (d, 1H, J=12.04 Hz, Cl₃CCH₂), 5.23 (d, 1H,J=12.03 Hz, Cl₃CCH₂), 5.37 (p, 1H, J=2.62 Hz, H2b), 5.77 (d, 1H, J=8.95Hz, H11), 6.74 (s, 1H, H9), 7.28 (s, 1H, H6); ¹³C NMR (CDCl₃, 100 MHz) δ170.3 (C═O), 167.9 (C5), 153.5 (OC═ONH), 151.0 (C8), 148.9 (C7), 128.0(C9-10), 125.4 (C5-6), 112.9 (C9), 110.6 (C6), 95.2 (Cl₃C), 88.2 (C11),74.7 (Cl₃CCH₂), 71.7 (C2), 60.5 (C11a), 56.1 (CH₃O7), 56.9 (CH₃O8), 51.2(C3), 36.2 (C1), 25.5 (C(CH₃)₃) 21.0 (C═OCH₃), 17.8 (Cquat), −4.3 and−5.3 (Si(CH₃)₂); IR (film) 3023, 2956, 1738 (C═O), 1718 (OC═ON), 1644(NC═O), 1605, 1518, 1466, 1428, 1411, 1376, 1301, 1245, 1214, 1116,1075, 1041, 1023, 842, 784, 756, 730, 712 cm⁻¹; MS (EI) m/z (relativeintensity) 627 ([M+H]^(+.), 100).

(11S,11aS,2R)-7,8-Dimethoxy-2-hydroxy-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(25)

A solution of K₂CO₃ (732 mg, 5.30 mmol; 1.0 Equiv.) in water (15 mL) wasadded to a stirred solution of 24 (3.32 g, 5.30 mmol, 1.0 Equiv.) inMeOH (15 mL) and THF (5 mL). The mixture was stirred at room temperaturefor 5 h and then excess solvent was removed by rotary evaporation atreduced pressure. The remaining aqueous residue was neutralised to pH 7with 1N HCl and extracted with EtOAc (4×30 mL). The organic layers werecombined, washed with brine (50 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The resulting oil was subjected to flashchromatography (EtOAc) to afford 25 as a white glass (2.84 g, 92%):[α]_(D) ²²=+58.3° (c=0.587, CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 0.22 (s,6H, Si(CH₃)₂), 0.87 (s, 9H, C(CH₃)₃), 2.06-2.11 (m, 1H, H1b), 2.28-2.33(m, 1 H, H1a), 3.60 (dd, 1H, J=4.31, 12.67 Hz, H3b), 3.71 (q, 1H,J=7.42, 15.67 Hz, H11a), 3.88 (s, 6H, CH₃O8 and CH₃O7), 4.01 (d, 1H,J=12.93 Hz, H3a), 4.17 (d, 1H, J=12.03 Hz, Cl₃CCH₂), 4.58 (br s, 1H,H2b), 5.23 (d, 1H, J=12.03 Hz, Cl₃CCH₂), 5.54 (d, 1H, J=9.00 Hz, H11),6.73 (s, 1H, H9), 7.21 (s, 1H, H6); ¹³C NMR (CDCl₃, 125 MHz) δ 168.4(C5), 153.6 (OC═ONH), 151.9 (C8), 148.8 (C7), 128.0 (C9-10), 125.5(C5-6), 112.8 (C9), 110.5 (C6), 95.2 (Cl₃C), 88.2 (C11), 74.7 (Cl₃CCH₂),69.5 (C2), 60.8 (C11a), 56.0, 55.9 (CH₃O8 and CH₃O7), 54.0 (C3), 38.8(C1), 25.6 (C(CH₃)₃), 17.8 (Cquat), −4.2 and −5.2 (Si(CH₃)₂); IR (film)3400 (br OH), 2932, 1731 (OC═ON), 1629 (NC═O), 1604, 1515, 1456, 1430,1407, 1302, 1273, 1214, 1117, 1075, 987, 837, 754, 712, 638 cm⁻¹; MS(EI) m/z (relative intensity) 585 ([M+H]^(+.), 100).

(11S,11aS)-7,8-Dimethoxy-2-oxo-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(26)

Diodobenzene diacetate (2.44 g, 7.58 mmol, 1.78 Equiv.) and2,2,6,6-tetramethylpiperidine nitroxyl (TEMPO) (133 mg, 0.85 mmol, 0.2Equiv.) were added to a stirred solution of 25 (2.49 g, 4.26 mmol; 1.0Equiv.) in dry DCM (40 mL). The mixture was stirred at room temperaturefor 18 h and the reaction mixture was diluted with DAM (50 mL). Theorganic phase was washed with said sodium bisulphite (2×25 mL), brine(40 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flashchromatography (EtOAc/Petroleum ether 6:4) afforded 26 as a white glass.(2.26 g, 91%): [α]_(D) ²²=+95.0° (c=0.795, CHCl₃); ¹H NMR (CDCl₃, 500MHz) δ 0.22, 0.23 (two s, 6H, Si(CH₃)₂), 0.86 (s, 9H, C(CH₃)₃), 2.56(dd, 1H, J=3.12, 19.60, H1b), 2.96 (dd, 1H, J=10.29, 18.9, H1a), 3.90(s, 3H, CH₃O8), 3.95-3.99 (m, 5H, H3b, H11a and CH₃O7), 4.21 (d, 1H,J=12.02 Hz, Cl₃CCH₂), 4.32 (d, 1H, J=20.93 Hz, H3a), 5.24 (d, 1H,J=12.03 Hz, Cl₃CCH₂), 5.83 (d, 1H, J=9.26 Hz, H11), 6.77 (s, 1H, H9),7.25 (s, 1H, H6); ¹³C NMR (CDCl₃, 125 MHz) δ 207.8 (C2), 168.0 (C5),153.7 (OC═ONH), 151.4 (C8), 149.2 (C7), 128.0 (C9-10), 124.5 (C5-6),113.0 (C9), 110.4 (C6), 95.1 (Cl₃C), 87.4 (C11), 74.8 (Cl₃CCH₂), 58.9(C11a), 56.2 (CH₃O7), 56.0 (CH₃O8), 52.8 (C3), 40.3 (C1), 25.5(C(CH₃)₃), 17.8 (Cquat), −4.2 and −5.3 (Si(CH₃)₂); IR (film) 2934, 1763(C═O), 1720 (OC═ON), 1649 (NC═O), 1604, 1515, 1402, 1274, 1217, 1120,1075, 1002, 866, 834, 756, 712 cm⁻¹; MS (EI) m/z (relative intensity)615 ([M+MeOH]^(+.), 100).

(11S,11aS)-7,8-Dimethoxy-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-2-[[(trifluoromethyl)sulfonyl]oxy]-1,2,3,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(27)

Pyridine (1.71 mL; 21.17 mmol; 7 Equiv.) and trifluoromethanesulfonicanhydride (3.56 mL; 21.17 mmol; 7 Equiv) were added to a stirredsolution of 27 (1.76 g, 3.02 mmol; 1 Equiv.) in dry CHCl₃ (50 mL) at0-5° C. (ice bath). The ice bath was removed and the reaction mixturewas stirred at room temperature for 3 h. At this point TLC analysisrevealed the persistence of starting material. As a result, one extraequivalent of pyridine and Tf₂O was added (0.24 and 0.51 mL,respectively). The reaction was stirred for an additional 1 h untilcomplete consumption of the starting material was observed by TLC. Thereaction mixture was washed with water, sat^(d) CuSO₄, sat^(d) NaHCO₃,dried (MgSO₄), filtered and the solvent was evaporated in vacuo. Theresulting residue was purified by flash chromatography (EtOAc/Petroleumether 2:8) to give 27 as a pale yellow glass (1.12 g, 52%): [α]_(D)²²=+56.2° (c=0.587, CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 0.25, 0.27 (two s,6H, Si(CH₃)₂), 0.88 (s, 9H, C(CH₃)₃), 2.82 (dd, 1H, J=2.79, 16.66 Hz,H1b), 3.33 (ddd, 1H, J=1.96, 10.73, 16.59 Hz, H1a), 3.90 (s, 3H, CH₃O8),3.94 (s, 3H, CH₃O7), 3.88-3.96 (m, 1H, H11a), 4.20 (d, 1H, J=12.00 Hz,Cl₃CCH₂), 5.23 (d, 1H, J=12.00 Hz, Cl₃CCH₂), 5.93 (d, 1H, J=9.26 Hz,H11), 6.74 (s, 1H, H9), 7.17 (s, 1H, H3), 7.23 (s, 1H, H6); ¹³C NMR(CDCl₃, 125 MHz) δ 164.9 (C5), 153.6 (OC═ONH), 151.8 (C8), 149.3 (C7),136.0 (C2), 127.9 (C9-10), 123.8 (C5-6), 121.0 (C3), 119.8 (CF₃), 113.2(C9), 110.7 (C6), 95.1 (Cl₃C), 86.4 (C11), 74.9 (Cl₃CCH₂), 60.6 (C11a),56.2 (CH₃O7), 56.0 (CH₃O8), 34.4 (C1), 25.5 (C(CH₃)₃), 17.8 (Cquat),−4.2 and −5.4 (Si(CH₃)₂); IR (film) 3008, 2930, 2858, 1725 (OC═ON), 1651(NC═O), 1516, 1423, 1214, 1136, 1078, 897, 835, 783, 760, 713, 642 cm⁻¹;MS (EI) m/z (relative intensity) 715 ([M+H]^(+.), 100).

Example 7(11aS)-7,8-Dimethoxy-2-(1-propenyl)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(29)(11S,11aS)-7,8-Dimethoxy-11-(tert-butyldimethylsilyloxymethyl)-10-(2,2,2-trichloroethoxycarbonyl)-2-(1-propenyl)-1,2,3,10,11,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(28)

A mixture of Et₃N (0.34 mL, 2.48 mmol, 3 Equiv.), water (0.5 mL) andEtOH (1.70 mL) was added to a solution of 27 (590 mg, 0.826 mmol, 1Equiv.) in toluene (1.70 mL) with vigorous stirring. The reactionmixture was treated with trans-propenylboronic acid (92.2 mg, 1.07 mmol,1.3 Equiv.) and Pd(PPh₃)₄ (19 mg, 0.016 mmol, 0.02 Equiv.). After 2 hstirring at room temp TLC revealed no reaction. The mixture was thenheated to reflux (111° C.) for 30 min after which time TLC showed thecomplete consumption of starting material. The reaction mixture wasallowed to cool to room temperature and diluted with EtOAc (30 mL). Theorganic phase was extracted with water (20 mL), brine (20 mL), dried(MgSO₄), filtered and the solvent was evaporated in vacuo. The resultingresidue was purified by flash chromatography (EtOAc/Petroleum ether 2:8)to afford the product 10 (297 mg, 59%): [α]_(D) ²²=+78.2° (c=0.582,CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 0.24, 0.26 (two s, 6H, Si(CH₃)₂), 0.89(s, 9H, C(CH₃)₃), 1.83 (dd, 3H, J=0.79, 6.69 Hz, H14), 2.58 (dd, 1H,J=3.11, 16.45 Hz, H1b), 3.06 (dd, 1H, J=10.59, 16.40 Hz, H1a), 3.82-3.88(m, 1H, H11a), 3.89 (s, 3H. CH₃O8), 3.94 (s, 3H, CH₃O7), 4.17 (d, 1H,J=12.04 Hz, Cl₃CCH₂), 5.23 (d, 1H, J=12.04 Hz, Cl₃CCH₂), 5.50-5.56 (m,1H, H13), 5.84 (d, 1H, J=8.86 Hz, H11), 6.25 (d, 1H, J=14.80 Hz, H12),6.75 (s, 1H, H9), 6.88 (s, 1H, H3), 7.24 (s, 1H, H6); ¹³C NMR (CDCl₃,125 MHz) δ 163.6 (C5), 153.6 (OC═ONH), 151.1 (C8), 149.0 (C7), 127.9(C9-10), 126.5 (C13), 125.5 (C5-6), 124.7 (C12), 124.6 (C3), 123.6 (C2),113.0 (C9), 110.5 (C6), 95.2 (Cl₃C), 87.2 (C11), 74.7 (Cl₃CCH₂), 61.4(C11a), 56.2 (CH₃O7), 56.0 (CH₃O8), 33.9 (C1), 25.6 (C(CH₃)₃), 18.4(C14), 17.9 (Cquat), −4.2 and −5.1 (Si (CH₃)₂); IR (film) 2961, 2935,2858, 1723 (OC═ON), 1648 (NC═O), 1514, 1404, 1272, 1216, 1076, 837, 756,644 cm⁻¹; MS (EI) m/z (relative intensity) 607 ([M+H]^(+.), 100).

(11aS)-7,8-Dimethoxy-2-(1-propenyl)-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one(29)

10% Cd/Pd couple (418 mg, 3.38 mmol, 8.2 Equiv.) was added to a rapidlystirring mixture of 28 (250 mg, 0.412 mmol, 1 Equiv.), THF (3 mL) and 1N ammonium acetate (3 mL). The reaction mixture was allowed to stir for3.5 h when TLC showed the complete consumption of the starting material.The solids were filtered and rinsed with H₂O and DAM. The aqueous layerwas extracted with DCM (3×30 mL) and the organic extracts were combined,washed with brine (50 mL), dried (MgSO₄), filtered and evaporated invacuo to provide the crude product. Purification by flash columnchromatography (0.5%→2% MeOH in CHCl₃) afforded 29 as a yellow glass (96mg, 78%): [α]_(D) ²⁴=+989° (c=0.890, CHCl₃); ¹H NMR (CDCl₃, 400 MHz) δ1.85 (d, 3H, J=6.26 Hz, H14), 3.12 (dd, 1H, J=4.95, 16.27 Hz, H1b), 3.30(dd, 1H, J=11.80, 15.27 Hz, H1a), 3.93 (s, 3H, CH₃O8), 3.95 (s, 3H,CH₃O7), 4.30 (dt, J=4.95, 15.70 Hz, H11a), 5.55-5.65 (m, 1H, H13), 6.27(d, J=16.04 Hz, H12), 6.81 (s, 1H, H9), 6.92 (s, 1H, H3), 7.50 (s, 1H,H6), 7.82 (d, 1H, J=4.00 Hz, H11); ¹³C NMR (CDCl₃, 100 MHz) δ 162.7(C11), 161.2 (C5), 151.8 (C8), 147.7 (C7), 140.4 (C9-10), 126.9 (C13),124.46, 124.43 (C12 and C3), 123.9 (C2), 119.2 (C5-6), 111.6 (C6), 109.8(C9), 56.18, 56.11 (CH₃O7 and (CH₃O8), 53.8 (C11a), 34.2 (C1), 18.4(C14); IR (film) 3018, 2997, 2930, 2847, 1610, 1598 (C═O), 1507, 1431,1344, 1254, 1214, 1101, 1065, 959, 862, 779 cm⁻¹; MS (EI) m/z (relativeintensity) 331 ([M+MeOH]^(+.), 100), 299 ([M+H]^(+.), 45).

Example 8 Parallel Synthesis of C2-Substituted PBDs (30a-al)

(i) A solution of triethylamine (0.12 mL, 6 equiv.) in water (0.2 mL)and ethanol (1.0 mL) was poured into a stirred solution of 27 (100 mg,0.14 mmol, 1 Equiv.) in toluene (1.0 mL) in an Emrys™ Process vial. Tothe solution was added the appropriate boronic acid (1.07 equiv.) andpolystyrene triphenylphosphine palladium (0) PS-PPh₃Pd (15 mg, 0.0014mmol, 0.01 Equiv). The vial was sealed with a Reseal™ septum, and thesuspension then irradiated at 100° C. for 20 minutes under microwaveradiation using an EmryS™ Optimizer Microwave Station when TLC showedabsence of starting material. N,N-diethanolaminomethyl polystyrenePS-DEAM (87.5 mg, 0.14 mmol, 1.0 equiv. [13 equiv. on boronic acidexcess]) was added to the reaction, and the suspension was irradiated at100° C. for 10 minutes under microwave radiation (as above). Water (3mL) was added to the reaction, and the suspension shaken for 10 minutes.The mixture was then transferred to a phase separator (PS) cartridgefitted with a selectively permeable frit pre-conditioned with CH₂Cl₂ (3mL) and coupled to a Na₂SO₄ cartridge. Extraction with CH₂Cl₂ (3×5 mL),followed by concentration in vacuo yielded an oil which was redissolvedin THF (1.5 mL) and 1N ammonium acetate (1.5 mL).

(ii) To the mixture resulting from the previous step was added 10% Cd/Pb(140 mg, 1.12 mmol, 8.0 Equiv.) while vigorously stirring and thereaction was kept for 1 hour at room temperature when TLC showed absenceof starting material. The mixture was poured into an identical PScartridge pre-conditioned with CH₂Cl₂ (3 mL) and coupled to a Na₂SO₄cartridge. Extraction with CH₂Cl₂ (3×5 mL) followed by concentration invacuo gave an oil which was subjected to flash chromatography(EtOAc:Hexane 1:1) afforded the desired compounds, which are listedbelow.

Yield Compound R″ (%)^(†) [α]_(D)* 30a Phenyl 62 +1012°  30b4-methylphenyl 39 +916° 30c 2-methylphenyl 38 +802° 30d 4-ethylphenyl 45+985° 30e 2,6-dimethylphenyl 35 +549° 30f 4-methoxyphenyl  99^(‡) +976°30g 3-methoxyphenyl — +825° 30h 4-tert-butylphenyl 35 +781° 30i4-fluorophenyl 41 +978° 30j 4-chlorophenyl 67 +796° 30k 4-biphenyl 44+792° 30l 4-phenoxyphenyl 47 +823° 30m 2-naphthyl 47 +720° 30n3,4-methylenedioxyphenyl 46 +837° 30o trans-2-(4-methylphenyl)vinyl 58+990° 30p 2-thiophenyl 59 +974° 30q trans-propenyl  78^(‡) +989° 30r4-dimethylaminophenyl 44 +858° 30s 4-methylthiophenyl 18 +979° 30t4-vinylphenyl 36 +796° 30u 3,4-dichlorophenyl 41 +641° 30v4-trifluoromethylphenyl 28 +785° 30w 4-isopropylphenyl 44 +985° 30x4-cyanophenyl 42 +1000°  30y 3-pyridinyl 14 +1200°  30z 4-pyridinyl 27+859° 30aa 4-formylphenyl 42 +928° 30ab 4-carboxylphenyl 43 — 30ac2,6-dimethoxyphenyl   18.5 — 30ad 4-acetanilide   26.3 — 30ae4-aminophenyl   21.3 — 30af 1-naphthyl 32 — 30ag 5-indole 34 — 30ah3-aminophenyl 41 — 30ai 2,6-difluorophenyl 14 — 30aj 1-pyrenyl 39 — 30ak4-hydroxyphenyl 14 — 30al trans-hexenyl — — ^(†)Overall yield, includingSuzuki coupling followed by imine formation. ^(‡)yield calculated fromTroc-deprotection final step only. *Concentration range: 0.047-0.89g/100 mL; Temp.: 20-29° C. All samples were dissolved in HPLC gradechloroform stabilised with amylene, purchased from Fisher Chemicals,Leicestershire, UK..

Example 9 Determination of In Vitro Cytotoxicity

K562 human chronic myeloid leukaemia cells were maintained in RPM1 1640medium supplemented with 10% fetal calf serum and 2 mM glutamine at 37°C. in a humidified atmosphere containing 5% CO₂ and were incubated witha specified dose of drug for 1 hour or 96 hours at 37° C. in the dark.The incubation was terminated by centrifugation (5 min, 300 g) and thecells were washed once with drug-free medium. Following the appropriatedrug treatment, the cells were transferred to 96-well microtiter plates(10⁴ cells per well, 8 wells per sample). Plates were then kept in thedark at 37° C. in a humidified atmosphere containing 5% CO₂. The assayis based on the ability of viable cells to reduce a yellow solubletetrazolium salt,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT,Aldrich-Sigma), to an insoluble purple formazan precipitate. Followingincubation of the plates for 4 days (to allow control cells to increasein number by approximately 10 fold), 20 μL of MTT solution (5 mg/mL inphosphate-buffered saline) was added to each well and the plates furtherincubated for 5 h. The plates were then centrifuged for 5 min at 300 gand the bulk of the medium pipetted from the cell pellet leaving 10-20μL per well. DMSO (200 μL) was added to each well and the samplesagitated to ensure complete mixing. The optical density was then read ata wavelength of 550 nm on a Titertek Multiscan ELISA plate reader, and adose-response curve was constructed. For each curve, an IC₅₀ value wasread as the dose required to reduce the final optical density to 50% ofthe control value.

Results

The following compounds showed an IC₅₀ of less than 1 μM after a 96 hourincubation period: 30a, 30b, 30c, 30d, 30f, 30g, 30h, 30i, 30j, 30k,30l, 30m, 30n, 30o, 30p, 30q, 30r, 30s, 30t, 30u, 30v, 30w, 30x, 30y,30z, 30aa, 30ac, 30ad, 30ae, 30af, 30ag, 30ah, 30ai, 30aj, 30al.

The following compounds showed an IC₅₀ of less than 10 nM after a 96hour incubation period: 30a, 30b, 30c, 30g, 30i, 30n, 30p, 30q, 30ai.

Compound IC₅₀ ^(b) (μM) ZC-204 3.80 ± 0.44 ZC-207 0.0053 ± 0.0049 ZC-209<0.01 ZC-211 <0.01 ^(b)1 hour incubation

1. A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein: R⁶ and R⁹ areindependently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, nitro,Me₃Sn and halo; R and R′ are independently selected from optionallysubstituted C₁₋₁₂ alkyl, C₃₋₂₀ heterocyclyl and C₅₋₂₀ aryl groups; thecompound being a dimer with each monomer being of formula (III), wherethe R⁸ of each monomer form together a dimer bridge having the formula—X—R″—X— linking the monomers, where R″ is a C₃₋₁₂ alkylene group, whichchain may be interrupted by one or more heteroatoms and/or aromaticrings, and each X is independently selected from O, S, or NH, and R⁷ isselected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, nitro, Me₃Sn andhalo, or any pair of adjacent groups from R⁶ to R⁹ together form a group—O—(CH₂)_(p)—O—, where p is 1 or 2; either R¹⁰ and R¹⁶ together form adouble bond between N10 and C11, or R¹⁰ is H and R¹⁶ is OH; R¹⁵ is anoptionally substituted C₅₋₂₀ aryl group, wherein the optionalsubstituents are independently selected from the group consisting ofC₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₂₀ heterocyclyl, C₅₋₂₀ aryl, halo,hydroxyl, —OR¹ wherein R¹ is a C₁₋₇ alkyl group or C₃₋₂₀ heterocyclylgroup or C₅₋₁₀ aryl group, alkoxy, —CH(OR¹)(OR²) wherein R¹ is asdefined above and R² is independently a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group or R¹ and R² together with thetwo oxygen atoms to which they are attached form a heterocyclic ringhaving from 4 to 8 ring atoms, —CH(OH)(OR¹) wherein R¹ is as definedabove, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy,thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR¹ wherein R¹is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido,acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino,nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano,isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone,—S(═O)OH, —SO₂H, —S(═O)₂OH, —SO₃H, sulfinate, sulfonate, sulfinyloxy,sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino,sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR¹⁷)₂wherein R¹⁷ is —H or C₁₋₇ alkyl group or C₃₋₂₀ heterocyclyl group orC₅₋₂₀ aryl group, phosphonooxy, —PO(═O)(OR¹⁷)₂ wherein R¹⁷ is as definedabove, —OP(OH)₂, phosphate, phosphoramidite, and phosphoramidate; andwherein heteroatoms of the heterocyclyl groups and the optionalheteroatoms of the alkylene groups are independently selected from thegroup consisting of N, S, and O.
 2. A compound according to claim 1,wherein the dimer bridge has the formula —O—(CH₂)_(n)—O— linking themonomers, where n is from 3 to
 12. 3. A compound according to claim 2,wherein n is from 3 to
 7. 4. A compound according to claim 1, whereinR¹⁰ and R¹⁶ together form a double bond between N10 and C11.
 5. Acompound according to claim 1, wherein R⁹ is H.
 6. A compound accordingto claim 1, wherein R⁷ and R⁸ are independently selected from H, OH, OR,SH, NH₂, NHR, NRR′ and halo.
 7. A pharmaceutical composition containinga compound of claim 1, and a pharmaceutically acceptable carrier ordiluent.
 8. A method of treatment of chronic myeloid leukemia,comprising administering to a subject in need of treatment atherapeutically-effective amount of a compound of claim
 1. 9. A methodof synthesizing a compound of formula III:

comprising reacting a compound of formula I:

with a compound of formula z-R¹⁵ in a coupling reaction, wherein R⁶ andR⁹ are independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′,nitro, Me₃Sn and halo; R and R′ are independently selected fromoptionally substituted C₁₋₁₂ alkyl, C₃₋₂₀ heterocyclyl and C₅₋₂₀ arylgroups; R⁷ and R⁸ are independently selected from H, R, OH, OR, SH, SR,NH₂, NHR, NRR′, nitro, Me₃Sn and halo, or the compound is a dimer witheach monomer being of formula (I), where the R⁷ groups or R⁸ groups ofeach monomers form together a dimer bridge having the formula —X—R″—X—linking the monomers, where R″ is a C₃₋₁₂ alkylene group, which chainmay be interrupted by one or more heteroatoms and/or aromatic rings, andeach X is independently selected from O, S, or NH; or any pair ofadjacent groups from R⁶ to R⁹ together form a group —O—(CH₂)_(p)—O—,where p is 1 or 2; R¹⁰ is a carbamate-based nitrogen protecting group;R² is a labile leaving group; R¹⁶ is either O—R¹¹, where R¹¹ is anoxygen protecting group, or OH, or R¹⁰ and R¹⁶ together form a doublebond between N10 and C11; z-R¹⁵ is any reactant suitable for a couplingreaction; R¹⁵ is an optionally substituted C₅₋₂₀ aryl group, wherein theoptional substituents are independently selected from the groupconsisting of C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₂₀ heterocyclyl, C₅₋₂₀aryl, halo, hydroxyl, —OR wherein R is a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group, alkoxy, —CH(OR¹)(OR²) wherein R¹is as defined above and R² is independently a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group or R¹ and R² together with thetwo oxygen atoms to which they are attached form a heterocyclic ringhaving from 4 to 8 ring atoms, —CH(OH)(OR¹) wherein R¹ is as definedabove, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy,thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR¹ wherein R¹is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido,acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino,nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano,isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone,—S(═O)OH, SO₂H, —S(═O)₂OH, —SO₃H, sulfinate, sulfonate, sulfinyloxy,sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino,sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR¹⁷)₂wherein R¹⁷ is —H or C₁₋₇ alkyl group or C₃₋₂₀ heterocyclyl group orC₅₋₂₀ aryl group, phosphonooxy, —PO(═O)(OR¹⁷)₂ wherein R¹⁷ is as definedabove, —OP(OH)₂, phosphate, phosphoramidite, and phosphoramidate; andwherein heteroatoms of the heterocyclyl groups and the optionalheteroatoms of the alkylene groups are independently selected from thegroup consisting of N, S, and O.
 10. A method according to claim 9,wherein the synthesis of said compound of formula III uses a palladiumcatalysed coupling step.
 11. A method according to claim 10, wherein thepalladium catalyst is Pd(PPh₃)₄, Pd(OCOCH₃)₂, PdCl₂ or Pd(dba)₃.
 12. Amethod according to claim 10, wherein the coupling reaction is performedunder microwave conditions.
 13. A method according to claim 10, whereinthe palladium catalyst is solid supported.
 14. A compound of formula III

and salts and solvates thereof, wherein: R⁶ and R⁹ are independentlyselected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, nitro, Me₃Sn andhalo; R and R′ are independently selected from optionally substitutedC₁₋₁₂ alkyl, C₃₋₂₀ heterocyclyl and C₅₋₂₀ aryl groups; the compoundbeing a dimer with each monomer being of formula (III), where the R⁸groups of each monomer form together a dimer bridge having the formula—X—R″—X— linking the monomers, where R″ is a C₃₋₁₂ alkylene group, whichchain may be interrupted by one or more heteroatoms and/or aromaticrings, and each X is independently selected from O, S, or NH, and R⁷ isselected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, nitro, Me₃Sn andhalo; or any pair of adjacent groups from R⁶ to R⁹ together form a group—O—(CH₂)_(p)—O—, where p is 1 or 2; R¹⁰ is a carbamate-based nitrogenprotecting group; R¹⁶ is —O—R¹¹, where R¹¹ is an oxygen protecting groupor H; R¹⁵ is an optionally substituted C₅₋₂₀ aryl group, wherein theoptional substituents are independently selected from the groupconsisting of C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₂₀ heterocyclyl, C₅₋₂₀aryl, halo, hydroxyl, —OR wherein R is a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group, alkoxy, —CH(OR¹)(OR²) wherein R¹is as defined above and R² is independently a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group or R¹ and R² together with thetwo oxygen atoms to which they are attached form a heterocyclic ringhaving from 4 to 8 ring atoms, —CH(OH)(OR¹) wherein R¹ is as definedabove, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy,thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR¹ wherein R¹is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido,acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino,nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano,isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone,—S(═O)OH, SO₂H, —S(═O)₂OH, —SO₃H, sulfinate, sulfonate, sulfinyloxy,sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino,sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR¹⁷)₂wherein R¹⁷ is H or C₁₋₇ alkyl group or C₃₋₂₀ heterocyclyl group orC₅₋₂₀ aryl group, phosphonooxy, —PO(═O)(OR¹⁷)₂ wherein R¹⁷ is as definedabove, —OP(OH)₂, phosphate, phosphoramidite, and phosphoramidate; andwherein heteroatoms of the heterocyclyl groups and the optionalheteroatoms of the alkylene groups are independently selected from thegroup consisting of N, S, and O.
 15. A compound according to claim 14,wherein R¹⁰ is Troc.
 16. A compound according to claim 14, wherein R¹¹is a silyl oxygen protecting group or THP.
 17. A compound of formula I:

for use in the synthesis of a compound of formula III:

wherein: R⁶ and R⁹ are independently selected from H, R, OH, OR, SH, SR,NH₂, NHR, NRR′, nitro, Me₃Sn and halo; R and R′ are independentlyselected from optionally substituted C₁₋₁₂ alkyl, C₃₋₂₀ heterocyclyl andC₅₋₂₀ aryl groups; R⁷ is selected from H, R, OH, OR, SH, SR, NH₂, NHR,NRR′, nitro, Me₃Sn and halo, the compound of formula III being dimerwith each monomer being of formula III, where the R⁸ groups of eachmonomer form together a dimer bridge having the formula —X—R″—X— linkingthe monomers, where R″ is a C₃₋₁₂ alkylene group, which chain may beinterrupted by one or more heteroatoms and/or aromatic rings, and each Xis independently selected from O, S, or NH; or any pair of adjacentgroups from R⁶ to R⁹ together form a group —O—(CH₂)_(p)—O—, where p is 1or 2; R¹⁰ is a carbamate-based nitrogen protecting group, or either R¹⁰and R¹⁶ together form a double bond between N10 and C11, or R¹⁰ is H andR¹⁶ is OH; R¹¹ is an oxygen protecting group or H; R² is a labileleaving group; R¹⁵ is an optionally substituted C₅₋₂₀ aryl group,wherein the optional substituents are independently selected from thegroup consisting of C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₂₀ heterocyclyl,C₅₋₂₀ aryl, halo, hydroxyl, —OR wherein R is a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group, alkoxy, —CH(OR¹)(OR²) wherein R¹is as defined above and R² is independently a C₁₋₇ alkyl group or C₃₋₂₀heterocyclyl group or C₅₋₁₀ aryl group or R¹ and R² together with thetwo oxygen atoms to which they are attached form a heterocyclic ringhaving from 4 to 8 ring atoms, —CH(OH)(OR¹) wherein R¹ is as definedabove, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy,thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR¹ wherein R¹is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido,acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino,nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano,isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone,—S(═O)OH, SO₂H, —S(═O)₂OH, —SO₃H, sulfinate, sulfonate, sulfinyloxy,sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino,sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR¹⁷)₂wherein R¹⁷ is —H or C₁₋₇ alkyl group or C₃₋₂₀ heterocyclyl group orC₅₋₂₀ aryl group, phosphonooxy, —PO(═O)(OR¹⁷)₂ wherein R¹⁷ is as definedabove, —OP(OH)₂, phosphate, phosphoramidite, and phosphoramidate; andwherein heteroatoms of the heterocyclyl groups and the optionalheteroatoms of the alkylene groups are independently selected from thegroup consisting of N, S, and O.
 18. A compound according to claim 6,wherein R⁷ is OR.
 19. A compound according to claim 6, wherein R⁷ isOMe.
 20. A compound according to claims 1 wherein R¹⁵ is a C₅₋₂₀ arylgroup optionally substituted with a substituent selected from the groupconsisting of R, OH, OR, NH₂, NHR, NRR′, ON, C(═O)H, C(═O)OH and halo.21. A compound according to claim 1, wherein R¹⁵ is a C₅₋₂₀ aryl groupsubstituted by OR.
 22. A compound according to claim 1, wherein R¹⁵ is aC₅₋₂₀aryl group substituted by OMe.
 23. A compound according to claim 1,wherein R⁶ is H, R⁷ is OMe, X is O, R″ is (CH₂)₃, R⁹ is H, R¹⁰ and R¹⁶together form a double bond between N10 and C11, and R¹⁵ ispara-methoxyphenyl.
 24. The compound of claim 1, wherein R″ is aC₃₋₁₂alkylene group interrupted by one or more heteroatoms, wherein theone or more heteroatoms are independently selected from the groupconsisting of O, S, and N.
 25. A compound of the following formula:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1, wherein R and R′ are unsubstituted.
 27. The compound of claim 1,wherein R¹⁵ is an unsubstituted C₅₋₂₀ aryl group.
 28. The compound ofclaim 1, wherein R¹⁵ is a singly substituted C₅₋₂₀ aryl group.